Optimal diagnosis and treatment of psychiatric illness requires clinicians to be able to connect mental and physical symptoms. Direct brain neurotransmitter testing is presently in its infancy and the science of defining the underlying mechanisms of psychiatric disorders lags behind the obvious clinical needs. We are not yet equipped to clearly recognize which neurotransmitters cause which symptoms. In this article series, we suggest an indirect way of judging neurotransmitter activity by recognizing specific mental and physical symptoms connected by common biology. Here we present hypothetical clinical cases to emphasize a possible way of analyzing symptoms in order to identify underlying pathology and guide more effective treatment. The descriptions we present in this series do not reflect the entire set of symptoms caused by the neurotransmitters we discuss; we created them based on what is presently known (or suspected). Additional research is needed to confirm or disprove the hypothesis we present. We argue that in cases of multiple psychiatric disorders and chronic pain, the development and approval of medications currently is based on an umbrella descriptive diagnoses, and disregards the various underlying causes of such conditions. Similar to how the many types of pneumonias are treated differently depending on the infective agent, we suggested the same possible causative approach to various types of depression and pain.

Part 1 of this series (Current Psychiatry, May 2022) looked into serotonin- and dopamine-associated symptoms. In Part 2 (Current Psychiatry, June 2022), we presented cases related to endorphin and norepinephrine dysfunction. We conclude the series by exploring gamma aminobutyric acid (GABA)- and glutamate-based clinical symptoms. Table 1 outlines medical and psychiatric symptoms that likely reflect GABA excess^1-9 and deficiency,^1-4,6,9-17 and Table 2 lists symptoms that likely reflect glutamate excess^9,18-31 and deficiency.^9,32-38 It is essential to note that both the quantity of neurotransmitters as well as the quality of the transmission (as in receptors, cellular pumps, and distribution mechanisms) are important.

GABA excess (Table 1^1-9)

Ms. V is brought to your office by a friend. She complains of pain all over her body, itchiness, inability to focus, and dizziness.^1,5,6,9 She is puzzled by how little pain she feels when she cuts her finger but by how much pain she is in every day, though her clinicians have not discovered a reason for her pain.^1,6,9 She states that her fatigue is so severe that she can sleep 15 hours a day.^1-6,9 Her obstructive and central sleep apnea have been treated, but this did not improve her fatigue.^3,5,9 She is forgetful and has been diagnosed with depression, though she says she does not feel depressed.^1,5,6 Nothing is pleasant to her, but she is prone to abnormal excitement and unpredictable behavior.^1,4,6,7

A physical exam shows slow breathing, bradycardia, decreased deep tendon reflexes, and decreased muscle tone.^1,5,6,9 Ms. V complains of double vision^1,5,6,9 and problems with gait and balance,^5,6,9 as well as tremors.^1,4-7 She experienced enuresis well into adulthood^1,5,6,9 and is prone to weight gain, dyspepsia, and constipation.^8,9 She cannot understand people who have anxiety, and is prone to melancholy.^4-6,9 Ms. V had been treated with electroconvulsive therapy in the past but states that she “had to have so much electricity, they gave up on me.”

Impression. Ms. V exhibits multiple symptoms associated with GABA excess. Dopaminergic medications such as methylphenidate or amphetamines may be helpful, as they suppress GABA. GABAergic medications and supplements should be avoided in such a patient. Noradrenergic medications including antidepressants with corresponding activity or vasopressors may be beneficial. Suppression of glutamate increases GABA, which is why ketamine in any formulation should be avoided in a patient such as Ms. V.

GABA deficiency (Table 1^1-4,6,9-17)

Mr. N complains of depression,^{1,3,4,6,12,16} pain all over his body, tingling in his hands and feet,^1,6,9 a constant dull headache,² and severe insomnia.^2,3,9,10 He cannot control his anxiety and, in general, has problems relaxing. In the office, he is jumpy, tremulous, and fidgety during the interview and examination.^1,3,4,6,9,12 His muscle tone is high^1,9,11 and he feels stiff.^6,9 Mr. N’s pupils are narrow^1,9; he is hyper-reflexive^1,9,11 and reports “Klonopin withdrawal seizures.”^1,6,9 He loves alcohol because “it makes me feel good” and helps with his mind, which otherwise “never stops.”^1,6,13 Mr. N is frequently anxious and very sensitive to pain, especially when he is upset. He was diagnosed with fibromyalgia by his primary care doctor, who says that irritable bowel is common in patients like him.^1,6 His anxiety disables him.^1-4,6,9-12 His sister reports that in addition to having difficulty relaxing, Mr. N is easily frustrated and sleeps poorly because he says he has racing thoughts.¹⁰ She mentions that her brother’s gambling addiction endangered his finances on several occasions^4,12,15 and he was suspected of having autism spectrum disorder.^4,12 Mr. N is frequently overwhelmed, including during your interview.^1,3,4,6 He is sensitive to light and noise^1,9 and complains of palpitations^1,3,4,6,9 and frequent shortness of breath.^1,3,4,9 He mentions his hands and feet often are cold, especially when he is anxious.^1,3,4,6,9 Not eating at regular times makes his symptoms even worse. Mr. N commonly feels depressed, but his anxiety is more bothersome.^{1,3,4,6,12,16} His ongoing complaints include difficulty concentrating and memory problems,^3,4,12,13 as well as a constant feeling of being overwhelmed.^1,3,4,6 His restless leg syndrome requires ongoing treatment.^1,9,14 Though uncommon, Mr. N has episodes of slowing and weakness, which are associated with growth hormone problems.¹⁶ In the past, he experienced gut motility dysregulation^9,10 and prolonged bleeding that worried his doctors.¹⁷

Impression. Mr. N shows multiple symptoms associated with GABA deficiency. The deficiency of GABA activity ultimately causes an increase in norepinephrine and dopamine firing; therefore, symptoms of GABA deficiency are partially aligned with symptoms of dopamine and norepinephrine excess. GABAergic medications would be most beneficial for such patients. Anticonvulsants (eg, gabapentin and pregabalin) are preferable. Acamprostate may be considered. For long-term use, benzodiapines are as problematic as opioids and should be avoided, if possible. The use of opioids in such patients is especially counter­productive. Some supplements and vitamins may enhance GABA activity. Avoiding bupropion and stimulants would be wise. Ketamine in any formulation would be a good choice in this scenario. Sedating antipsychotic medications have a promise for patients such as Mr. N. The muscle relaxant baclofen frequently helps with these patients’ pain, anxiety, and sleep.

Continue to: Glutamate excess

Mr. B is anxious and bites his fingernails and cheek while you interview him.¹⁸ He has scars on his lower arms that were caused by years of picking his skin.¹⁸ He complains of headache^28-30 and deep muscle, whole body,^19-23 and abdominal pain.²⁰ Both hyperesthesia (he calls it “fibromyalgia”)^9,19,20,22 and irritable bowel syndrome flare up if he eats Chinese food that contains monosodium glutamate.²¹ This also increases nausea, vomiting, and hypertensive episodes.^{9,19,20,22,24,26} Mr. B developed and received treatment for opioid use disorder after being prescribed morphine for the treatment of fibromyalgia.²² He is being treated for posttraumatic stress disorder at the VA hospital and is bitter that his flashbacks are not controlled.²³ Once, he experienced a frank psychosis.²⁶ He commonly experiences dissociative symptoms and suicidality.^23,26 The sensations of crawling skin,¹⁸ panic attacks, and nightmares complicate his life.²³ Mr. B is angry that his “incompetent” psychiatrist stopped his diazepam and that it “almost killed him” by causing delirium.²⁴ He suffers from severe neuropathic pain in his feet and says that his pain, depression, and anxiety respond especially well to ketamine treatment.^9,23,26 He is prone to euphoria and has had several manic episodes.²⁶ In childhood, his parents brought him to a psychiatrist to address episodes of head-banging and self-hitting.¹⁸ Mr. B developed seizures; presently, they are controlled, but he remains chronically dizzy.^9,24,25,27 He claims that his headaches and migraines respond only to methadone and that sumatriptan makes them worse, especially in prolonged treatment.^28-30 He is tachycardic, tremulous, and makes you feel deeply uneasy.^9,24

Impression. Mr. B has many symptoms of glutamate hyperactivity. The use of N-methyl-D-aspartate receptor antagonists such as memantine and dextromethorphan and alpha-blockers (eg, clonidine and tizanidine) may be considered. Avoiding addictive substances would be prudent, though the use of ketamine seems rational. Anticonvulsants are recommended, along with sedating antidepressants. Serotonin-norepinephrine reuptake inhibitors may not be the best choice because norepinephrine potentiates glutamate function. Dopamine inhibits glutamate, so stimulants, bupropion, and amantadine³¹ may be paradoxically applied to treatment of both cognitive and physical symptoms (including pain) in a patient with glutamate hyperactivity.

Glutamate deficiency (Table 2^9,32-38)

Mr. Z feels dull, fatigued, and unhappy.^32,33,37 He is overweight and moves slowly. Sometimes he is so slow and clumsy that he seems obtunded.^9,36,37 He states that his peripheral neuropathy does not cause him pain, though his neurodiagnostic results are unfavorable.³² Mr. Z’s overall pain threshold is high, and he is unhappy with people who complain about pain because “who cares?”³² His memory and concentration were never good.^33,37,38 He suffers from insomnia and is frequently miserable and disheartened.^32,33,38 People view him as melancholic.^33,37 Mr. Z is mildly depressed, but he experiences aggressive outbursts^37,38 and bouts of anxiety,^32,33,36,38 psychosis, and mania.^33,37,38 He is visibly confused³⁷ and says it is easy for him to get disoriented and lost.^37,38 His medical history includes long-term constipation and several episodes of ileus.^9,34,35 His childhood-onset seizures are controlled presently.³³ He complains of frequent bouts of dizziness and headache.^32,34,35 On physical exam, Mr. Z has dry mouth, hypotension, diminished deep tendon reflexes, and bradycardia.^9,34,35 He sought a consultation from an ophthalmologist to evaluate an eye movement problem.^33,36 No cause was found, but the ophthalmologist thought this problem might have the same underlying mechanism as his dysarthria.³³ Mr. Z’s balance is bothersome, but his podiatrist was unable to help him to correct his abnormal gait.^33-36 A friend who came with Mr. Z mentioned she had noticed personality changes in him over the last several months.³⁷

Impression. Mr. Z exhibits multiple signs of low glutamatergic function. Amino acid taurine has been shown in rodents to increase brain levels of both GABA and glutamate. Glutamate is metabolized into GABA, so low glutamate and low GABA symptoms overlap. Glutamine, which is present in meat, fish, eggs, dairy, wheat, and some vegetables, is converted in the body into glutamate and may be considered for a patient with low glutamate function. The medication approach to such a patient would be similar to the treatment of a low GABA patient and includes glutamate-enhancing magnesium and dextromethorphan.

Rarely is just 1 neurotransmitter involved

Most real-world patients have mixed presentations with more than 1 neurotransmitter implicated in the pathology of their symptoms. A clinician’s ability to dissect the clinical picture and select an appropriate treatment must be based on history and observed behavior because no lab results or reliable tests are presently available.

Continue to: The most studied...

The most studied neurotransmitter in depression and anxiety is serotonin, and for many years psychiatrists have paid too much attention to it. Similarly, pain physicians have been overly focused on the opioid system. Excessive attention to these neurochemicals has overshadowed multiple other (no less impactful) neuro­transmitters. Dopamine is frequently not attended to by many physicians who treat chronic pain. Psychiatrists also may overlook underlying endorphin or glutamate dysfunction in patients with psychiatric illness.

Nonpharmacologic approaches can affect neurotransmitters

With all the emphasis on pharmacologic treatments, it is important to remember that nonpharmacologic modalities such as exercise, diet, hydrotherapy, acupuncture, and psychotherapy can help normalize neurotransmitter function in the brain and ultimately help patients with chronic conditions. Careful use of nutritional supplements and vitamins may also be beneficial.

A hypothesis for future research

Multiple peripheral and central mechanisms define various chronic pain and psychiatric symptoms and disorders, including depression, anxiety, and fibromyalgia. The variety of mechanisms of pathologic mood and pain perception may be expressed to a different extent and in countless combinations in individual patients. This, in part, explains the variable responses to the same treatment observed in similar patients, or even in the same patient.

Clinicians should always remember that depression and anxiety as well as chronic pain (including fibromyalgia and chronic headache) are not a representation of a single condition but are the result of an assembly of different syndromes; therefore, 1 treatment does not fit all patients. Pain is ultimately recognized and comprehended centrally, making it very much a neuropsychiatric field. The optimal treatment for 2 patients with similar pain or psychiatric symptoms may be drastically different due to different underlying mechanisms that can be distinguished by looking at the symptoms other than “pain” or “depression.”

Remembering that every neurotransmitter deficiency or excess has an identifiable clinical correlation is important. Basing a treatment approach on a specific clinical presentation in a particular depressed or chronic pain patient would assure a more successful and reliable outcome.

Continue to: This 3-part series...

This 3-part series was designed to bring attention to a notion that diagnosis and treatment of diverse conditions such as “depression,” “anxiety,” or “chronic pain” should be based on clinically identifiable symptoms that may suggest specific neurotransmitter(s) involved in a specific type of each of these conditions. However, there are no well-recognized, well-established, reliable, or validated syndromes described in this series. The collection of symptoms associated with the various neuro­transmitters described in this series is not complete. We have assembled what is described in the literature as a suggestion for future research.

Bottom Line

Both high and low levels of gamma aminobutyric acid (GABA) and glutamate may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.

Related Resources

• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (part 1). Current Psychiatry. 2022;21(5):30-36. doi:10.12788/cp.0242
• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (part 2). Current Psychiatry. 2022;21(6):28-33. doi:10.12788/cp.0253

Drug Brand Names

Acamprostate • Campral
Amantadine • Gocovri
Bupropion • Wellbutrin
Clonazepam • Klonopin
Clonidine • Catapres
Diazepam • Valium
Gabapentin • Neurontin
Ketamine • Ketalar
Memantine • Namenda
Methylphenidate • Concerta
Morphine • Kadian
Pregabalin • Lyrica
Sumatriptan • Imitrex
Tizanidine • Zanaflex

Optimal diagnosis and treatment of psychiatric illness requires clinicians to be able to connect mental and physical symptoms. Direct brain neurotransmitter testing is presently in its infancy and the science of defining the underlying mechanisms of psychiatric disorders lags behind the obvious clinical needs. We are not yet equipped to clearly recognize which neurotransmitters cause which symptoms. In this article series, we suggest an indirect way of judging neurotransmitter activity by recognizing specific mental and physical symptoms connected by common biology. Here we present hypothetical clinical cases to emphasize a possible way of analyzing symptoms in order to identify underlying pathology and guide more effective treatment. The descriptions we present in this series do not reflect the entire set of symptoms caused by the neurotransmitters we discuss; we created them based on what is presently known (or suspected). Additional research is needed to confirm or disprove the hypothesis we present. We argue that in cases of multiple psychiatric disorders and chronic pain, the development and approval of medications currently is based on an umbrella descriptive diagnoses, and disregards the various underlying causes of such conditions. Similar to how the many types of pneumonias are treated differently depending on the infective agent, we suggested the same possible causative approach to various types of depression and pain.

Part 1 of this series (Current Psychiatry, May 2022) looked into serotonin- and dopamine-associated symptoms. In Part 2 (Current Psychiatry, June 2022), we presented cases related to endorphin and norepinephrine dysfunction. We conclude the series by exploring gamma aminobutyric acid (GABA)- and glutamate-based clinical symptoms. Table 1 outlines medical and psychiatric symptoms that likely reflect GABA excess^1-9 and deficiency,^1-4,6,9-17 and Table 2 lists symptoms that likely reflect glutamate excess^9,18-31 and deficiency.^9,32-38 It is essential to note that both the quantity of neurotransmitters as well as the quality of the transmission (as in receptors, cellular pumps, and distribution mechanisms) are important.

GABA excess (Table 1^1-9)

Ms. V is brought to your office by a friend. She complains of pain all over her body, itchiness, inability to focus, and dizziness.^1,5,6,9 She is puzzled by how little pain she feels when she cuts her finger but by how much pain she is in every day, though her clinicians have not discovered a reason for her pain.^1,6,9 She states that her fatigue is so severe that she can sleep 15 hours a day.^1-6,9 Her obstructive and central sleep apnea have been treated, but this did not improve her fatigue.^3,5,9 She is forgetful and has been diagnosed with depression, though she says she does not feel depressed.^1,5,6 Nothing is pleasant to her, but she is prone to abnormal excitement and unpredictable behavior.^1,4,6,7

A physical exam shows slow breathing, bradycardia, decreased deep tendon reflexes, and decreased muscle tone.^1,5,6,9 Ms. V complains of double vision^1,5,6,9 and problems with gait and balance,^5,6,9 as well as tremors.^1,4-7 She experienced enuresis well into adulthood^1,5,6,9 and is prone to weight gain, dyspepsia, and constipation.^8,9 She cannot understand people who have anxiety, and is prone to melancholy.^4-6,9 Ms. V had been treated with electroconvulsive therapy in the past but states that she “had to have so much electricity, they gave up on me.”

Impression. Ms. V exhibits multiple symptoms associated with GABA excess. Dopaminergic medications such as methylphenidate or amphetamines may be helpful, as they suppress GABA. GABAergic medications and supplements should be avoided in such a patient. Noradrenergic medications including antidepressants with corresponding activity or vasopressors may be beneficial. Suppression of glutamate increases GABA, which is why ketamine in any formulation should be avoided in a patient such as Ms. V.

GABA deficiency (Table 1^1-4,6,9-17)

Mr. N complains of depression,^{1,3,4,6,12,16} pain all over his body, tingling in his hands and feet,^1,6,9 a constant dull headache,² and severe insomnia.^2,3,9,10 He cannot control his anxiety and, in general, has problems relaxing. In the office, he is jumpy, tremulous, and fidgety during the interview and examination.^1,3,4,6,9,12 His muscle tone is high^1,9,11 and he feels stiff.^6,9 Mr. N’s pupils are narrow^1,9; he is hyper-reflexive^1,9,11 and reports “Klonopin withdrawal seizures.”^1,6,9 He loves alcohol because “it makes me feel good” and helps with his mind, which otherwise “never stops.”^1,6,13 Mr. N is frequently anxious and very sensitive to pain, especially when he is upset. He was diagnosed with fibromyalgia by his primary care doctor, who says that irritable bowel is common in patients like him.^1,6 His anxiety disables him.^1-4,6,9-12 His sister reports that in addition to having difficulty relaxing, Mr. N is easily frustrated and sleeps poorly because he says he has racing thoughts.¹⁰ She mentions that her brother’s gambling addiction endangered his finances on several occasions^4,12,15 and he was suspected of having autism spectrum disorder.^4,12 Mr. N is frequently overwhelmed, including during your interview.^1,3,4,6 He is sensitive to light and noise^1,9 and complains of palpitations^1,3,4,6,9 and frequent shortness of breath.^1,3,4,9 He mentions his hands and feet often are cold, especially when he is anxious.^1,3,4,6,9 Not eating at regular times makes his symptoms even worse. Mr. N commonly feels depressed, but his anxiety is more bothersome.^{1,3,4,6,12,16} His ongoing complaints include difficulty concentrating and memory problems,^3,4,12,13 as well as a constant feeling of being overwhelmed.^1,3,4,6 His restless leg syndrome requires ongoing treatment.^1,9,14 Though uncommon, Mr. N has episodes of slowing and weakness, which are associated with growth hormone problems.¹⁶ In the past, he experienced gut motility dysregulation^9,10 and prolonged bleeding that worried his doctors.¹⁷

Impression. Mr. N shows multiple symptoms associated with GABA deficiency. The deficiency of GABA activity ultimately causes an increase in norepinephrine and dopamine firing; therefore, symptoms of GABA deficiency are partially aligned with symptoms of dopamine and norepinephrine excess. GABAergic medications would be most beneficial for such patients. Anticonvulsants (eg, gabapentin and pregabalin) are preferable. Acamprostate may be considered. For long-term use, benzodiapines are as problematic as opioids and should be avoided, if possible. The use of opioids in such patients is especially counter­productive. Some supplements and vitamins may enhance GABA activity. Avoiding bupropion and stimulants would be wise. Ketamine in any formulation would be a good choice in this scenario. Sedating antipsychotic medications have a promise for patients such as Mr. N. The muscle relaxant baclofen frequently helps with these patients’ pain, anxiety, and sleep.

Continue to: Glutamate excess

Mr. B is anxious and bites his fingernails and cheek while you interview him.¹⁸ He has scars on his lower arms that were caused by years of picking his skin.¹⁸ He complains of headache^28-30 and deep muscle, whole body,^19-23 and abdominal pain.²⁰ Both hyperesthesia (he calls it “fibromyalgia”)^9,19,20,22 and irritable bowel syndrome flare up if he eats Chinese food that contains monosodium glutamate.²¹ This also increases nausea, vomiting, and hypertensive episodes.^{9,19,20,22,24,26} Mr. B developed and received treatment for opioid use disorder after being prescribed morphine for the treatment of fibromyalgia.²² He is being treated for posttraumatic stress disorder at the VA hospital and is bitter that his flashbacks are not controlled.²³ Once, he experienced a frank psychosis.²⁶ He commonly experiences dissociative symptoms and suicidality.^23,26 The sensations of crawling skin,¹⁸ panic attacks, and nightmares complicate his life.²³ Mr. B is angry that his “incompetent” psychiatrist stopped his diazepam and that it “almost killed him” by causing delirium.²⁴ He suffers from severe neuropathic pain in his feet and says that his pain, depression, and anxiety respond especially well to ketamine treatment.^9,23,26 He is prone to euphoria and has had several manic episodes.²⁶ In childhood, his parents brought him to a psychiatrist to address episodes of head-banging and self-hitting.¹⁸ Mr. B developed seizures; presently, they are controlled, but he remains chronically dizzy.^9,24,25,27 He claims that his headaches and migraines respond only to methadone and that sumatriptan makes them worse, especially in prolonged treatment.^28-30 He is tachycardic, tremulous, and makes you feel deeply uneasy.^9,24

Impression. Mr. B has many symptoms of glutamate hyperactivity. The use of N-methyl-D-aspartate receptor antagonists such as memantine and dextromethorphan and alpha-blockers (eg, clonidine and tizanidine) may be considered. Avoiding addictive substances would be prudent, though the use of ketamine seems rational. Anticonvulsants are recommended, along with sedating antidepressants. Serotonin-norepinephrine reuptake inhibitors may not be the best choice because norepinephrine potentiates glutamate function. Dopamine inhibits glutamate, so stimulants, bupropion, and amantadine³¹ may be paradoxically applied to treatment of both cognitive and physical symptoms (including pain) in a patient with glutamate hyperactivity.

Glutamate deficiency (Table 2^9,32-38)

Mr. Z feels dull, fatigued, and unhappy.^32,33,37 He is overweight and moves slowly. Sometimes he is so slow and clumsy that he seems obtunded.^9,36,37 He states that his peripheral neuropathy does not cause him pain, though his neurodiagnostic results are unfavorable.³² Mr. Z’s overall pain threshold is high, and he is unhappy with people who complain about pain because “who cares?”³² His memory and concentration were never good.^33,37,38 He suffers from insomnia and is frequently miserable and disheartened.^32,33,38 People view him as melancholic.^33,37 Mr. Z is mildly depressed, but he experiences aggressive outbursts^37,38 and bouts of anxiety,^32,33,36,38 psychosis, and mania.^33,37,38 He is visibly confused³⁷ and says it is easy for him to get disoriented and lost.^37,38 His medical history includes long-term constipation and several episodes of ileus.^9,34,35 His childhood-onset seizures are controlled presently.³³ He complains of frequent bouts of dizziness and headache.^32,34,35 On physical exam, Mr. Z has dry mouth, hypotension, diminished deep tendon reflexes, and bradycardia.^9,34,35 He sought a consultation from an ophthalmologist to evaluate an eye movement problem.^33,36 No cause was found, but the ophthalmologist thought this problem might have the same underlying mechanism as his dysarthria.³³ Mr. Z’s balance is bothersome, but his podiatrist was unable to help him to correct his abnormal gait.^33-36 A friend who came with Mr. Z mentioned she had noticed personality changes in him over the last several months.³⁷

Impression. Mr. Z exhibits multiple signs of low glutamatergic function. Amino acid taurine has been shown in rodents to increase brain levels of both GABA and glutamate. Glutamate is metabolized into GABA, so low glutamate and low GABA symptoms overlap. Glutamine, which is present in meat, fish, eggs, dairy, wheat, and some vegetables, is converted in the body into glutamate and may be considered for a patient with low glutamate function. The medication approach to such a patient would be similar to the treatment of a low GABA patient and includes glutamate-enhancing magnesium and dextromethorphan.

Rarely is just 1 neurotransmitter involved

Most real-world patients have mixed presentations with more than 1 neurotransmitter implicated in the pathology of their symptoms. A clinician’s ability to dissect the clinical picture and select an appropriate treatment must be based on history and observed behavior because no lab results or reliable tests are presently available.

Continue to: The most studied...

The most studied neurotransmitter in depression and anxiety is serotonin, and for many years psychiatrists have paid too much attention to it. Similarly, pain physicians have been overly focused on the opioid system. Excessive attention to these neurochemicals has overshadowed multiple other (no less impactful) neuro­transmitters. Dopamine is frequently not attended to by many physicians who treat chronic pain. Psychiatrists also may overlook underlying endorphin or glutamate dysfunction in patients with psychiatric illness.

Nonpharmacologic approaches can affect neurotransmitters

With all the emphasis on pharmacologic treatments, it is important to remember that nonpharmacologic modalities such as exercise, diet, hydrotherapy, acupuncture, and psychotherapy can help normalize neurotransmitter function in the brain and ultimately help patients with chronic conditions. Careful use of nutritional supplements and vitamins may also be beneficial.

A hypothesis for future research

Multiple peripheral and central mechanisms define various chronic pain and psychiatric symptoms and disorders, including depression, anxiety, and fibromyalgia. The variety of mechanisms of pathologic mood and pain perception may be expressed to a different extent and in countless combinations in individual patients. This, in part, explains the variable responses to the same treatment observed in similar patients, or even in the same patient.

Clinicians should always remember that depression and anxiety as well as chronic pain (including fibromyalgia and chronic headache) are not a representation of a single condition but are the result of an assembly of different syndromes; therefore, 1 treatment does not fit all patients. Pain is ultimately recognized and comprehended centrally, making it very much a neuropsychiatric field. The optimal treatment for 2 patients with similar pain or psychiatric symptoms may be drastically different due to different underlying mechanisms that can be distinguished by looking at the symptoms other than “pain” or “depression.”

Remembering that every neurotransmitter deficiency or excess has an identifiable clinical correlation is important. Basing a treatment approach on a specific clinical presentation in a particular depressed or chronic pain patient would assure a more successful and reliable outcome.

Continue to: This 3-part series...

This 3-part series was designed to bring attention to a notion that diagnosis and treatment of diverse conditions such as “depression,” “anxiety,” or “chronic pain” should be based on clinically identifiable symptoms that may suggest specific neurotransmitter(s) involved in a specific type of each of these conditions. However, there are no well-recognized, well-established, reliable, or validated syndromes described in this series. The collection of symptoms associated with the various neuro­transmitters described in this series is not complete. We have assembled what is described in the literature as a suggestion for future research.

Bottom Line

Both high and low levels of gamma aminobutyric acid (GABA) and glutamate may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.

Related Resources

• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (part 1). Current Psychiatry. 2022;21(5):30-36. doi:10.12788/cp.0242
• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (part 2). Current Psychiatry. 2022;21(6):28-33. doi:10.12788/cp.0253

Drug Brand Names

Acamprostate • Campral
Amantadine • Gocovri
Bupropion • Wellbutrin
Clonazepam • Klonopin
Clonidine • Catapres
Diazepam • Valium
Gabapentin • Neurontin
Ketamine • Ketalar
Memantine • Namenda
Methylphenidate • Concerta
Morphine • Kadian
Pregabalin • Lyrica
Sumatriptan • Imitrex
Tizanidine • Zanaflex

Optimal diagnosis and treatment of psychiatric illness requires clinicians to be able to connect mental and physical symptoms. Direct brain neurotransmitter testing is presently in its infancy and the science of defining the underlying mechanisms of psychiatric disorders lags behind the obvious clinical needs. We are not yet equipped to clearly recognize which neurotransmitters cause which symptoms. In this article series, we suggest an indirect way of judging neurotransmitter activity by recognizing specific mental and physical symptoms connected by common biology. Here we present hypothetical clinical cases to emphasize a possible way of analyzing symptoms in order to identify underlying pathology and guide more effective treatment. The descriptions we present in this series do not reflect the entire set of symptoms caused by the neurotransmitters we discuss; we created them based on what is presently known (or suspected). Additional research is needed to confirm or disprove the hypothesis we present. We argue that in cases of multiple psychiatric disorders and chronic pain, the development and approval of medications currently is based on an umbrella descriptive diagnoses, and disregards the various underlying causes of such conditions. Similar to how the many types of pneumonias are treated differently depending on the infective agent, we suggested the same possible causative approach to various types of depression and pain.

Part 1 of this series (Current Psychiatry, May 2022) looked into serotonin- and dopamine-associated symptoms. In Part 2 (Current Psychiatry, June 2022), we presented cases related to endorphin and norepinephrine dysfunction. We conclude the series by exploring gamma aminobutyric acid (GABA)- and glutamate-based clinical symptoms. Table 1 outlines medical and psychiatric symptoms that likely reflect GABA excess^1-9 and deficiency,^1-4,6,9-17 and Table 2 lists symptoms that likely reflect glutamate excess^9,18-31 and deficiency.^9,32-38 It is essential to note that both the quantity of neurotransmitters as well as the quality of the transmission (as in receptors, cellular pumps, and distribution mechanisms) are important.

GABA excess (Table 1^1-9)

Ms. V is brought to your office by a friend. She complains of pain all over her body, itchiness, inability to focus, and dizziness.^1,5,6,9 She is puzzled by how little pain she feels when she cuts her finger but by how much pain she is in every day, though her clinicians have not discovered a reason for her pain.^1,6,9 She states that her fatigue is so severe that she can sleep 15 hours a day.^1-6,9 Her obstructive and central sleep apnea have been treated, but this did not improve her fatigue.^3,5,9 She is forgetful and has been diagnosed with depression, though she says she does not feel depressed.^1,5,6 Nothing is pleasant to her, but she is prone to abnormal excitement and unpredictable behavior.^1,4,6,7

A physical exam shows slow breathing, bradycardia, decreased deep tendon reflexes, and decreased muscle tone.^1,5,6,9 Ms. V complains of double vision^1,5,6,9 and problems with gait and balance,^5,6,9 as well as tremors.^1,4-7 She experienced enuresis well into adulthood^1,5,6,9 and is prone to weight gain, dyspepsia, and constipation.^8,9 She cannot understand people who have anxiety, and is prone to melancholy.^4-6,9 Ms. V had been treated with electroconvulsive therapy in the past but states that she “had to have so much electricity, they gave up on me.”

Impression. Ms. V exhibits multiple symptoms associated with GABA excess. Dopaminergic medications such as methylphenidate or amphetamines may be helpful, as they suppress GABA. GABAergic medications and supplements should be avoided in such a patient. Noradrenergic medications including antidepressants with corresponding activity or vasopressors may be beneficial. Suppression of glutamate increases GABA, which is why ketamine in any formulation should be avoided in a patient such as Ms. V.

GABA deficiency (Table 1^1-4,6,9-17)

Mr. N complains of depression,^{1,3,4,6,12,16} pain all over his body, tingling in his hands and feet,^1,6,9 a constant dull headache,² and severe insomnia.^2,3,9,10 He cannot control his anxiety and, in general, has problems relaxing. In the office, he is jumpy, tremulous, and fidgety during the interview and examination.^1,3,4,6,9,12 His muscle tone is high^1,9,11 and he feels stiff.^6,9 Mr. N’s pupils are narrow^1,9; he is hyper-reflexive^1,9,11 and reports “Klonopin withdrawal seizures.”^1,6,9 He loves alcohol because “it makes me feel good” and helps with his mind, which otherwise “never stops.”^1,6,13 Mr. N is frequently anxious and very sensitive to pain, especially when he is upset. He was diagnosed with fibromyalgia by his primary care doctor, who says that irritable bowel is common in patients like him.^1,6 His anxiety disables him.^1-4,6,9-12 His sister reports that in addition to having difficulty relaxing, Mr. N is easily frustrated and sleeps poorly because he says he has racing thoughts.¹⁰ She mentions that her brother’s gambling addiction endangered his finances on several occasions^4,12,15 and he was suspected of having autism spectrum disorder.^4,12 Mr. N is frequently overwhelmed, including during your interview.^1,3,4,6 He is sensitive to light and noise^1,9 and complains of palpitations^1,3,4,6,9 and frequent shortness of breath.^1,3,4,9 He mentions his hands and feet often are cold, especially when he is anxious.^1,3,4,6,9 Not eating at regular times makes his symptoms even worse. Mr. N commonly feels depressed, but his anxiety is more bothersome.^{1,3,4,6,12,16} His ongoing complaints include difficulty concentrating and memory problems,^3,4,12,13 as well as a constant feeling of being overwhelmed.^1,3,4,6 His restless leg syndrome requires ongoing treatment.^1,9,14 Though uncommon, Mr. N has episodes of slowing and weakness, which are associated with growth hormone problems.¹⁶ In the past, he experienced gut motility dysregulation^9,10 and prolonged bleeding that worried his doctors.¹⁷

Impression. Mr. N shows multiple symptoms associated with GABA deficiency. The deficiency of GABA activity ultimately causes an increase in norepinephrine and dopamine firing; therefore, symptoms of GABA deficiency are partially aligned with symptoms of dopamine and norepinephrine excess. GABAergic medications would be most beneficial for such patients. Anticonvulsants (eg, gabapentin and pregabalin) are preferable. Acamprostate may be considered. For long-term use, benzodiapines are as problematic as opioids and should be avoided, if possible. The use of opioids in such patients is especially counter­productive. Some supplements and vitamins may enhance GABA activity. Avoiding bupropion and stimulants would be wise. Ketamine in any formulation would be a good choice in this scenario. Sedating antipsychotic medications have a promise for patients such as Mr. N. The muscle relaxant baclofen frequently helps with these patients’ pain, anxiety, and sleep.

Continue to: Glutamate excess

Mr. B is anxious and bites his fingernails and cheek while you interview him.¹⁸ He has scars on his lower arms that were caused by years of picking his skin.¹⁸ He complains of headache^28-30 and deep muscle, whole body,^19-23 and abdominal pain.²⁰ Both hyperesthesia (he calls it “fibromyalgia”)^9,19,20,22 and irritable bowel syndrome flare up if he eats Chinese food that contains monosodium glutamate.²¹ This also increases nausea, vomiting, and hypertensive episodes.^{9,19,20,22,24,26} Mr. B developed and received treatment for opioid use disorder after being prescribed morphine for the treatment of fibromyalgia.²² He is being treated for posttraumatic stress disorder at the VA hospital and is bitter that his flashbacks are not controlled.²³ Once, he experienced a frank psychosis.²⁶ He commonly experiences dissociative symptoms and suicidality.^23,26 The sensations of crawling skin,¹⁸ panic attacks, and nightmares complicate his life.²³ Mr. B is angry that his “incompetent” psychiatrist stopped his diazepam and that it “almost killed him” by causing delirium.²⁴ He suffers from severe neuropathic pain in his feet and says that his pain, depression, and anxiety respond especially well to ketamine treatment.^9,23,26 He is prone to euphoria and has had several manic episodes.²⁶ In childhood, his parents brought him to a psychiatrist to address episodes of head-banging and self-hitting.¹⁸ Mr. B developed seizures; presently, they are controlled, but he remains chronically dizzy.^9,24,25,27 He claims that his headaches and migraines respond only to methadone and that sumatriptan makes them worse, especially in prolonged treatment.^28-30 He is tachycardic, tremulous, and makes you feel deeply uneasy.^9,24

Impression. Mr. B has many symptoms of glutamate hyperactivity. The use of N-methyl-D-aspartate receptor antagonists such as memantine and dextromethorphan and alpha-blockers (eg, clonidine and tizanidine) may be considered. Avoiding addictive substances would be prudent, though the use of ketamine seems rational. Anticonvulsants are recommended, along with sedating antidepressants. Serotonin-norepinephrine reuptake inhibitors may not be the best choice because norepinephrine potentiates glutamate function. Dopamine inhibits glutamate, so stimulants, bupropion, and amantadine³¹ may be paradoxically applied to treatment of both cognitive and physical symptoms (including pain) in a patient with glutamate hyperactivity.

Glutamate deficiency (Table 2^9,32-38)

Mr. Z feels dull, fatigued, and unhappy.^32,33,37 He is overweight and moves slowly. Sometimes he is so slow and clumsy that he seems obtunded.^9,36,37 He states that his peripheral neuropathy does not cause him pain, though his neurodiagnostic results are unfavorable.³² Mr. Z’s overall pain threshold is high, and he is unhappy with people who complain about pain because “who cares?”³² His memory and concentration were never good.^33,37,38 He suffers from insomnia and is frequently miserable and disheartened.^32,33,38 People view him as melancholic.^33,37 Mr. Z is mildly depressed, but he experiences aggressive outbursts^37,38 and bouts of anxiety,^32,33,36,38 psychosis, and mania.^33,37,38 He is visibly confused³⁷ and says it is easy for him to get disoriented and lost.^37,38 His medical history includes long-term constipation and several episodes of ileus.^9,34,35 His childhood-onset seizures are controlled presently.³³ He complains of frequent bouts of dizziness and headache.^32,34,35 On physical exam, Mr. Z has dry mouth, hypotension, diminished deep tendon reflexes, and bradycardia.^9,34,35 He sought a consultation from an ophthalmologist to evaluate an eye movement problem.^33,36 No cause was found, but the ophthalmologist thought this problem might have the same underlying mechanism as his dysarthria.³³ Mr. Z’s balance is bothersome, but his podiatrist was unable to help him to correct his abnormal gait.^33-36 A friend who came with Mr. Z mentioned she had noticed personality changes in him over the last several months.³⁷

Impression. Mr. Z exhibits multiple signs of low glutamatergic function. Amino acid taurine has been shown in rodents to increase brain levels of both GABA and glutamate. Glutamate is metabolized into GABA, so low glutamate and low GABA symptoms overlap. Glutamine, which is present in meat, fish, eggs, dairy, wheat, and some vegetables, is converted in the body into glutamate and may be considered for a patient with low glutamate function. The medication approach to such a patient would be similar to the treatment of a low GABA patient and includes glutamate-enhancing magnesium and dextromethorphan.

Rarely is just 1 neurotransmitter involved

Most real-world patients have mixed presentations with more than 1 neurotransmitter implicated in the pathology of their symptoms. A clinician’s ability to dissect the clinical picture and select an appropriate treatment must be based on history and observed behavior because no lab results or reliable tests are presently available.

Continue to: The most studied...

The most studied neurotransmitter in depression and anxiety is serotonin, and for many years psychiatrists have paid too much attention to it. Similarly, pain physicians have been overly focused on the opioid system. Excessive attention to these neurochemicals has overshadowed multiple other (no less impactful) neuro­transmitters. Dopamine is frequently not attended to by many physicians who treat chronic pain. Psychiatrists also may overlook underlying endorphin or glutamate dysfunction in patients with psychiatric illness.

Nonpharmacologic approaches can affect neurotransmitters

With all the emphasis on pharmacologic treatments, it is important to remember that nonpharmacologic modalities such as exercise, diet, hydrotherapy, acupuncture, and psychotherapy can help normalize neurotransmitter function in the brain and ultimately help patients with chronic conditions. Careful use of nutritional supplements and vitamins may also be beneficial.

A hypothesis for future research

Multiple peripheral and central mechanisms define various chronic pain and psychiatric symptoms and disorders, including depression, anxiety, and fibromyalgia. The variety of mechanisms of pathologic mood and pain perception may be expressed to a different extent and in countless combinations in individual patients. This, in part, explains the variable responses to the same treatment observed in similar patients, or even in the same patient.

Clinicians should always remember that depression and anxiety as well as chronic pain (including fibromyalgia and chronic headache) are not a representation of a single condition but are the result of an assembly of different syndromes; therefore, 1 treatment does not fit all patients. Pain is ultimately recognized and comprehended centrally, making it very much a neuropsychiatric field. The optimal treatment for 2 patients with similar pain or psychiatric symptoms may be drastically different due to different underlying mechanisms that can be distinguished by looking at the symptoms other than “pain” or “depression.”

Remembering that every neurotransmitter deficiency or excess has an identifiable clinical correlation is important. Basing a treatment approach on a specific clinical presentation in a particular depressed or chronic pain patient would assure a more successful and reliable outcome.

Continue to: This 3-part series...

This 3-part series was designed to bring attention to a notion that diagnosis and treatment of diverse conditions such as “depression,” “anxiety,” or “chronic pain” should be based on clinically identifiable symptoms that may suggest specific neurotransmitter(s) involved in a specific type of each of these conditions. However, there are no well-recognized, well-established, reliable, or validated syndromes described in this series. The collection of symptoms associated with the various neuro­transmitters described in this series is not complete. We have assembled what is described in the literature as a suggestion for future research.

Bottom Line

Both high and low levels of gamma aminobutyric acid (GABA) and glutamate may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.

Related Resources

• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (part 1). Current Psychiatry. 2022;21(5):30-36. doi:10.12788/cp.0242
• Arbuck DM, Salmerón JM, Mueller R. Neurotransmitter-based diagnosis and treatment: a hypothesis (part 2). Current Psychiatry. 2022;21(6):28-33. doi:10.12788/cp.0253

Drug Brand Names

Acamprostate • Campral
Amantadine • Gocovri
Bupropion • Wellbutrin
Clonazepam • Klonopin
Clonidine • Catapres
Diazepam • Valium
Gabapentin • Neurontin
Ketamine • Ketalar
Memantine • Namenda
Methylphenidate • Concerta
Morphine • Kadian
Pregabalin • Lyrica
Sumatriptan • Imitrex
Tizanidine • Zanaflex

Schizophrenia is arguably the most serious psychiatric brain syndrome. It disables teens and young adults and robs them of their potential and life dreams. It is widely regarded as a hopeless illness.

But it does not have to be. The reason most patients with schizophrenia do not return to their baseline is because obsolete clinical management approaches, a carryover from the last century, continue to be used.

Approximately 20 years ago, psychiatric researchers made a major discovery: psychosis is a neurotoxic state, and each psychotic episode is associated with significant brain damage in both gray and white matter.¹ Based on that discovery, a more rational management of schizophrenia has emerged, focused on protecting patients from experiencing psychotic recurrence after the first-episode psychosis (FEP). In the past century, this strategy did not exist because psychiatrists were in a state of scientific ignorance, completely unaware that the malignant component of schizophrenia that leads to disability is psychotic relapses, the primary cause of which is very poor medication adherence after hospital discharge following the FEP.

Based on the emerging scientific evidence, here are 3 essential principles to halt the deterioration and bend the curve of outcomes in schizophrenia:

1. Minimize the duration of untreated psychosis (DUP)

Numerous studies have shown that the longer the DUP, the worse the outcome in schizophrenia.^2,3 It is therefore vital to shorten the DUP spanning the emergence of psychotic symptoms at home, prior to the first hospital admission.⁴ The DUP is often prolonged from weeks to months by a combination of anosognosia by the patient, who fails to recognize how pathological their hallucinations and delusions are, plus the stigma of mental illness, which leads parents to delay bringing their son or daughter for psychiatric evaluation and treatment.

Another reason for a prolonged DUP is the legal system’s governing of the initiation of antipsychotic medications for an acutely psychotic patient who does not believe he/she is sick, and who adamantly refuses to receive medications. Laws passed decades ago have not kept up with scientific advances about brain damage during the DUP. Instead of delegating the rapid administration of an antipsychotic medication to the psychiatric physician who evaluated and diagnosed a patient with acute psychosis, the legal system further prolongs the DUP by requiring the psychiatrist to go to court and have a judge order the administration of antipsychotic medications. Such a legal requirement that delays urgently needed treatment has never been imposed on neurologists when administering medication to an obtunded stroke patient. Yet psychosis damages brain tissue and must be treated as urgently as stroke.⁵

Perhaps the most common reason for a long DUP is the recurrent relapses of psychosis, almost always caused by the high nonadherence rate among patients with schizophrenia due to multiple factors related to the illness itself.⁶ Ensuring uninterrupted delivery of an antipsychotic to a patient’s brain is as important to maintaining remission in schizophrenia as uninterrupted insulin treatment is for an individual with diabetes. The only way to guarantee ongoing daily pharmacotherapy in schizophrenia and avoid a longer DUP and more brain damage is to use long-acting injectable (LAI) formulations of antipsychotic medications, which are infrequently used despite making eminent sense to protect patients from the tragic consequences of psychotic relapse.⁷

Continue to: Start very early use of LAIs

2. Start very early use of LAIs

There is no doubt that switching from an oral to an LAI antipsychotic immediately after hospital discharge for the FEP is the single most important medical decision psychiatrists can make for patients with schizophrenia.⁸ This is because disability in schizophrenia begins after the second episode, not the first.^9-11 Therefore, psychiatrists must behave like cardiologists,¹² who strive to prevent a second destructive myocardial infarction. Regrettably, 99.9% of psychiatric practitioners never start an LAI after the FEP, and usually wait until the patient experiences multiple relapses, after extensive gray matter atrophy and white matter disintegration have occurred due to the neuro­inflammation and oxidative stress (free radicals) that occur with every psychotic episode.^13,14 This clearly does not make clinical sense, but remains the standard current practice.

In oncology, chemotherapy is far more effective in Stage 1 cancer, immediately after the diagnosis is made, rather than in Stage 4, when the prognosis is very poor. Similarly, LAIs are best used in Stage 1 schizophrenia, which is the first episode (schizophrenia researchers now regard the illness as having stages).¹⁵ Unfortunately, it is now rare for patients with schizophrenia to be switched to LAI pharmacotherapy right after recovery from the FEP. Instead, LAIs are more commonly used in Stage 3 or Stage 4, when the brains of patients with chronic schizophrenia have been already structurally damaged, and functional disability had set in. Bending the cure of outcome in schizophrenia is only possible when LAIs are used very early to prevent the second episode.

The prevention of relapse by using LAIs in FEP is truly remarkable. Subotnik et al¹⁶ reported that only 5% of FEP patients who received an LAI antipsychotic relapsed, compared to 33% of those who received an oral formulation of the same antipsychotic (a 650% difference). It is frankly inexplicable why psychiatrists do not exploit the relapse-preventing properties of LAIs at the time of discharge after the FEP, and instead continue to perpetuate the use of prescribing oral tablets to patients who are incapable of full adherence and doomed to “self-destruct.” This was the practice model in the previous century, when there was total ignorance about the brain-damaging effects of psychosis, and no sense of urgency about preventing psychotic relapses and DUP. Psychiatrists regarded LAIs as a last resort instead of a life-saving first resort.

In addition to relapse prevention,¹⁷ the benefits of second-generation LAIs include neuroprotection¹⁸ and lower all-cause mortality,¹⁹ a remarkable triad of benefits for patients with schizophrenia.²⁰

3. Implement comprehensive psychosocial treatment

Most patients with schizophrenia do not have access to the array of psychosocial treatments that have been shown to be vital for rehabilitation following the FEP, just as physical rehabilitation is indispensable after the first stroke. Studies such as RAISE,²¹ which was funded by the National Institute of Mental Health, have demonstrated the value of psychosocial therapies (Table^21-23). Collaborative care with primary care physicians is also essential due to the high prevalence of metabolic disorders (obesity, diabetics, dyslipidemia, hypertension), which tend to be undertreated in patients with schizophrenia.²⁴

Finally, when patients continue to experience delusions and hallucinations despite full adherence (with LAIs), clozapine must be used. Like LAIs, clozapine is woefully under­utilized²⁵ despite having been shown to restore mental health and full recovery to many (but not all) patients written off as hopeless due to persistent and refractory psychotic symptoms.²⁶

If clinicians who treat schizophrenia implement these 3 steps in their FEP patients, they will be gratified to witness a more benign trajectory of schizophrenia, which I have personally seen. The curve can indeed be bent in favor of better outcomes. By using the 3 evidence-based steps described here, clinicians will realize that schizophrenia does not have to carry the label of “the worst disease affecting mankind,” as an editorial in a top-tier journal pessimistically stated over 3 decades ago.²⁷

Schizophrenia is arguably the most serious psychiatric brain syndrome. It disables teens and young adults and robs them of their potential and life dreams. It is widely regarded as a hopeless illness.

But it does not have to be. The reason most patients with schizophrenia do not return to their baseline is because obsolete clinical management approaches, a carryover from the last century, continue to be used.

Approximately 20 years ago, psychiatric researchers made a major discovery: psychosis is a neurotoxic state, and each psychotic episode is associated with significant brain damage in both gray and white matter.¹ Based on that discovery, a more rational management of schizophrenia has emerged, focused on protecting patients from experiencing psychotic recurrence after the first-episode psychosis (FEP). In the past century, this strategy did not exist because psychiatrists were in a state of scientific ignorance, completely unaware that the malignant component of schizophrenia that leads to disability is psychotic relapses, the primary cause of which is very poor medication adherence after hospital discharge following the FEP.

Based on the emerging scientific evidence, here are 3 essential principles to halt the deterioration and bend the curve of outcomes in schizophrenia:

1. Minimize the duration of untreated psychosis (DUP)

Numerous studies have shown that the longer the DUP, the worse the outcome in schizophrenia.^2,3 It is therefore vital to shorten the DUP spanning the emergence of psychotic symptoms at home, prior to the first hospital admission.⁴ The DUP is often prolonged from weeks to months by a combination of anosognosia by the patient, who fails to recognize how pathological their hallucinations and delusions are, plus the stigma of mental illness, which leads parents to delay bringing their son or daughter for psychiatric evaluation and treatment.

Another reason for a prolonged DUP is the legal system’s governing of the initiation of antipsychotic medications for an acutely psychotic patient who does not believe he/she is sick, and who adamantly refuses to receive medications. Laws passed decades ago have not kept up with scientific advances about brain damage during the DUP. Instead of delegating the rapid administration of an antipsychotic medication to the psychiatric physician who evaluated and diagnosed a patient with acute psychosis, the legal system further prolongs the DUP by requiring the psychiatrist to go to court and have a judge order the administration of antipsychotic medications. Such a legal requirement that delays urgently needed treatment has never been imposed on neurologists when administering medication to an obtunded stroke patient. Yet psychosis damages brain tissue and must be treated as urgently as stroke.⁵

Perhaps the most common reason for a long DUP is the recurrent relapses of psychosis, almost always caused by the high nonadherence rate among patients with schizophrenia due to multiple factors related to the illness itself.⁶ Ensuring uninterrupted delivery of an antipsychotic to a patient’s brain is as important to maintaining remission in schizophrenia as uninterrupted insulin treatment is for an individual with diabetes. The only way to guarantee ongoing daily pharmacotherapy in schizophrenia and avoid a longer DUP and more brain damage is to use long-acting injectable (LAI) formulations of antipsychotic medications, which are infrequently used despite making eminent sense to protect patients from the tragic consequences of psychotic relapse.⁷

Continue to: Start very early use of LAIs

2. Start very early use of LAIs

There is no doubt that switching from an oral to an LAI antipsychotic immediately after hospital discharge for the FEP is the single most important medical decision psychiatrists can make for patients with schizophrenia.⁸ This is because disability in schizophrenia begins after the second episode, not the first.^9-11 Therefore, psychiatrists must behave like cardiologists,¹² who strive to prevent a second destructive myocardial infarction. Regrettably, 99.9% of psychiatric practitioners never start an LAI after the FEP, and usually wait until the patient experiences multiple relapses, after extensive gray matter atrophy and white matter disintegration have occurred due to the neuro­inflammation and oxidative stress (free radicals) that occur with every psychotic episode.^13,14 This clearly does not make clinical sense, but remains the standard current practice.

In oncology, chemotherapy is far more effective in Stage 1 cancer, immediately after the diagnosis is made, rather than in Stage 4, when the prognosis is very poor. Similarly, LAIs are best used in Stage 1 schizophrenia, which is the first episode (schizophrenia researchers now regard the illness as having stages).¹⁵ Unfortunately, it is now rare for patients with schizophrenia to be switched to LAI pharmacotherapy right after recovery from the FEP. Instead, LAIs are more commonly used in Stage 3 or Stage 4, when the brains of patients with chronic schizophrenia have been already structurally damaged, and functional disability had set in. Bending the cure of outcome in schizophrenia is only possible when LAIs are used very early to prevent the second episode.

The prevention of relapse by using LAIs in FEP is truly remarkable. Subotnik et al¹⁶ reported that only 5% of FEP patients who received an LAI antipsychotic relapsed, compared to 33% of those who received an oral formulation of the same antipsychotic (a 650% difference). It is frankly inexplicable why psychiatrists do not exploit the relapse-preventing properties of LAIs at the time of discharge after the FEP, and instead continue to perpetuate the use of prescribing oral tablets to patients who are incapable of full adherence and doomed to “self-destruct.” This was the practice model in the previous century, when there was total ignorance about the brain-damaging effects of psychosis, and no sense of urgency about preventing psychotic relapses and DUP. Psychiatrists regarded LAIs as a last resort instead of a life-saving first resort.

In addition to relapse prevention,¹⁷ the benefits of second-generation LAIs include neuroprotection¹⁸ and lower all-cause mortality,¹⁹ a remarkable triad of benefits for patients with schizophrenia.²⁰

3. Implement comprehensive psychosocial treatment

Most patients with schizophrenia do not have access to the array of psychosocial treatments that have been shown to be vital for rehabilitation following the FEP, just as physical rehabilitation is indispensable after the first stroke. Studies such as RAISE,²¹ which was funded by the National Institute of Mental Health, have demonstrated the value of psychosocial therapies (Table^21-23). Collaborative care with primary care physicians is also essential due to the high prevalence of metabolic disorders (obesity, diabetics, dyslipidemia, hypertension), which tend to be undertreated in patients with schizophrenia.²⁴

Finally, when patients continue to experience delusions and hallucinations despite full adherence (with LAIs), clozapine must be used. Like LAIs, clozapine is woefully under­utilized²⁵ despite having been shown to restore mental health and full recovery to many (but not all) patients written off as hopeless due to persistent and refractory psychotic symptoms.²⁶

If clinicians who treat schizophrenia implement these 3 steps in their FEP patients, they will be gratified to witness a more benign trajectory of schizophrenia, which I have personally seen. The curve can indeed be bent in favor of better outcomes. By using the 3 evidence-based steps described here, clinicians will realize that schizophrenia does not have to carry the label of “the worst disease affecting mankind,” as an editorial in a top-tier journal pessimistically stated over 3 decades ago.²⁷

Schizophrenia is arguably the most serious psychiatric brain syndrome. It disables teens and young adults and robs them of their potential and life dreams. It is widely regarded as a hopeless illness.

But it does not have to be. The reason most patients with schizophrenia do not return to their baseline is because obsolete clinical management approaches, a carryover from the last century, continue to be used.

Approximately 20 years ago, psychiatric researchers made a major discovery: psychosis is a neurotoxic state, and each psychotic episode is associated with significant brain damage in both gray and white matter.¹ Based on that discovery, a more rational management of schizophrenia has emerged, focused on protecting patients from experiencing psychotic recurrence after the first-episode psychosis (FEP). In the past century, this strategy did not exist because psychiatrists were in a state of scientific ignorance, completely unaware that the malignant component of schizophrenia that leads to disability is psychotic relapses, the primary cause of which is very poor medication adherence after hospital discharge following the FEP.

Based on the emerging scientific evidence, here are 3 essential principles to halt the deterioration and bend the curve of outcomes in schizophrenia:

1. Minimize the duration of untreated psychosis (DUP)

Numerous studies have shown that the longer the DUP, the worse the outcome in schizophrenia.^2,3 It is therefore vital to shorten the DUP spanning the emergence of psychotic symptoms at home, prior to the first hospital admission.⁴ The DUP is often prolonged from weeks to months by a combination of anosognosia by the patient, who fails to recognize how pathological their hallucinations and delusions are, plus the stigma of mental illness, which leads parents to delay bringing their son or daughter for psychiatric evaluation and treatment.

Another reason for a prolonged DUP is the legal system’s governing of the initiation of antipsychotic medications for an acutely psychotic patient who does not believe he/she is sick, and who adamantly refuses to receive medications. Laws passed decades ago have not kept up with scientific advances about brain damage during the DUP. Instead of delegating the rapid administration of an antipsychotic medication to the psychiatric physician who evaluated and diagnosed a patient with acute psychosis, the legal system further prolongs the DUP by requiring the psychiatrist to go to court and have a judge order the administration of antipsychotic medications. Such a legal requirement that delays urgently needed treatment has never been imposed on neurologists when administering medication to an obtunded stroke patient. Yet psychosis damages brain tissue and must be treated as urgently as stroke.⁵

Perhaps the most common reason for a long DUP is the recurrent relapses of psychosis, almost always caused by the high nonadherence rate among patients with schizophrenia due to multiple factors related to the illness itself.⁶ Ensuring uninterrupted delivery of an antipsychotic to a patient’s brain is as important to maintaining remission in schizophrenia as uninterrupted insulin treatment is for an individual with diabetes. The only way to guarantee ongoing daily pharmacotherapy in schizophrenia and avoid a longer DUP and more brain damage is to use long-acting injectable (LAI) formulations of antipsychotic medications, which are infrequently used despite making eminent sense to protect patients from the tragic consequences of psychotic relapse.⁷

Continue to: Start very early use of LAIs

2. Start very early use of LAIs

There is no doubt that switching from an oral to an LAI antipsychotic immediately after hospital discharge for the FEP is the single most important medical decision psychiatrists can make for patients with schizophrenia.⁸ This is because disability in schizophrenia begins after the second episode, not the first.^9-11 Therefore, psychiatrists must behave like cardiologists,¹² who strive to prevent a second destructive myocardial infarction. Regrettably, 99.9% of psychiatric practitioners never start an LAI after the FEP, and usually wait until the patient experiences multiple relapses, after extensive gray matter atrophy and white matter disintegration have occurred due to the neuro­inflammation and oxidative stress (free radicals) that occur with every psychotic episode.^13,14 This clearly does not make clinical sense, but remains the standard current practice.

In oncology, chemotherapy is far more effective in Stage 1 cancer, immediately after the diagnosis is made, rather than in Stage 4, when the prognosis is very poor. Similarly, LAIs are best used in Stage 1 schizophrenia, which is the first episode (schizophrenia researchers now regard the illness as having stages).¹⁵ Unfortunately, it is now rare for patients with schizophrenia to be switched to LAI pharmacotherapy right after recovery from the FEP. Instead, LAIs are more commonly used in Stage 3 or Stage 4, when the brains of patients with chronic schizophrenia have been already structurally damaged, and functional disability had set in. Bending the cure of outcome in schizophrenia is only possible when LAIs are used very early to prevent the second episode.

The prevention of relapse by using LAIs in FEP is truly remarkable. Subotnik et al¹⁶ reported that only 5% of FEP patients who received an LAI antipsychotic relapsed, compared to 33% of those who received an oral formulation of the same antipsychotic (a 650% difference). It is frankly inexplicable why psychiatrists do not exploit the relapse-preventing properties of LAIs at the time of discharge after the FEP, and instead continue to perpetuate the use of prescribing oral tablets to patients who are incapable of full adherence and doomed to “self-destruct.” This was the practice model in the previous century, when there was total ignorance about the brain-damaging effects of psychosis, and no sense of urgency about preventing psychotic relapses and DUP. Psychiatrists regarded LAIs as a last resort instead of a life-saving first resort.

In addition to relapse prevention,¹⁷ the benefits of second-generation LAIs include neuroprotection¹⁸ and lower all-cause mortality,¹⁹ a remarkable triad of benefits for patients with schizophrenia.²⁰

3. Implement comprehensive psychosocial treatment

Most patients with schizophrenia do not have access to the array of psychosocial treatments that have been shown to be vital for rehabilitation following the FEP, just as physical rehabilitation is indispensable after the first stroke. Studies such as RAISE,²¹ which was funded by the National Institute of Mental Health, have demonstrated the value of psychosocial therapies (Table^21-23). Collaborative care with primary care physicians is also essential due to the high prevalence of metabolic disorders (obesity, diabetics, dyslipidemia, hypertension), which tend to be undertreated in patients with schizophrenia.²⁴

Finally, when patients continue to experience delusions and hallucinations despite full adherence (with LAIs), clozapine must be used. Like LAIs, clozapine is woefully under­utilized²⁵ despite having been shown to restore mental health and full recovery to many (but not all) patients written off as hopeless due to persistent and refractory psychotic symptoms.²⁶

If clinicians who treat schizophrenia implement these 3 steps in their FEP patients, they will be gratified to witness a more benign trajectory of schizophrenia, which I have personally seen. The curve can indeed be bent in favor of better outcomes. By using the 3 evidence-based steps described here, clinicians will realize that schizophrenia does not have to carry the label of “the worst disease affecting mankind,” as an editorial in a top-tier journal pessimistically stated over 3 decades ago.²⁷

Mr. T, age 34, is a veteran who recently returned to civilian life. He presents to his local Veteran Affairs facility for transition of care. During active duty, he had been diagnosed with obstructive sleep apnea, tobacco use disorder, posttraumatic stress disorder (PTSD) secondary to combat exposure, and insomnia. Mr. T says he wants to quit smoking; currently, he smokes 2 packs of cigarettes per day. The primary care clinician notes that Mr. T has uncontrolled PTSD symptoms and poor sleep, and refers him for an outpatient mental health appointment.

At the mental health appointment 3 weeks later, Mr. T asks about medications to quit smoking, specifically varenicline (Table 1¹). Mr. T’s PTSD Checklist for DSM-5 score is 52, which indicates severe PTSD symptomatology. He says he sees shadowy figures in his periphery every day, and worries they are spying on him. His wife reports Mr. T has had these symptoms for most of their 10-year marriage but has never been treated for them. After a discussion with the outpatient team, Mr. T says he is willing to engage in exposure therapy for PTSD, but he does not want to take any medications other than varenicline for smoking cessation.

Cigarette smoke is a known carcinogen and risk factor for the development of cardiovascular and respiratory diseases and other comorbidities. People with severe mental illness (SMI) are 3 to 5 times more likely to smoke, and they often face multiple barriers to cessation, including low socioeconomic status and lack of support.² Even when patients with SMI are provided appropriate behavioral and pharmacologic interventions, they often require more frequent monitoring and counseling, receive a longer duration of drug therapy, and experience lower smoking cessation rates than the general population.²

Current guidelines recommend nicotine replacement therapy (NRT), bupropion, varenicline, and behavioral support as first-line therapies for smoking cessation in patients with and without SMI.² Evidence suggests that varenicline is more effective than other pharmacologic options; however, in 2009 a black-box warning was added to both varenicline and bupropion to highlight an increased risk of neuropsychiatric events in individuals with SMI.² This led some clinicians to hesitate to prescribe varenicline or bupropion to patients with psychiatric illness. However, in 2016, the EAGLES trial evaluated the safety of varenicline, bupropion, and NRT in smokers with and without psychiatric disorders, and based on the findings, the black-box warning was removed.² 

This article reviews the evidence regarding the use of varenicline and the risk of neuropsychiatric adverse events in patients with psychiatric illness. Table 2^3-6 provides a summary of each varenicline trial we discuss.

The EAGLES trial

EAGLES was a multicenter, multinational, randomized, double-blind, triple-dummy, placebo- and active-controlled trial of 8,144 individuals who received treatment for smoking cessation.³ The primary endpoint was the incidence of a composite measure of moderate to severe neuropsychiatric events (NPSAEs).³ Participants were split into psychiatric (N = 4,116) and nonpsychiatric (N = 4,028) cohorts and randomized into 4 treatment arms: varenicline 1 mg twice a day, bupropion 150 mg twice a day, nicotine patch 21 mg/d with taper, or placebo, all for 12 weeks with an additional 12 weeks of follow-up. All participants smoked ≥10 cigarettes per day. Individuals in the psychiatric cohort had to be psychiatrically stable (no exacerbations for 6 months and stable treatment for 3 months). Exclusionary diagnoses included psychotic disorders (except schizophrenia and schizoaffective disorder), dementia, substance use (except nicotine), and personality disorders (except borderline personality disorder).²

The rates of moderate to severe NPSAEs in the varenicline groups were 1.25% (95% CI, 0.60 to 1.90) in the nonpsychiatric cohort and 6.42% (95% CI, 4.91 to 7.93) in the psychiatric cohort.³ However, when comparing the varenicline group of the psychiatric cohort to the other arms of the psychiatric cohort, there were no differences (bupropion 6.62% [95% CI, 5.09 to 8.15], nicotine patch 5.20% [95% CI, 3.84 to 6.56], placebo 4.83% [95% CI, 3.51 to 6.16], respectively). The primary efficacy endpoint was continuous abstinence rates (CAR) for Week 9 through Week 12. In the psychiatric cohort, varenicline was superior compared to placebo (odds ratio [OR] 3.24; 95% CI, 2.56 to 4.11), bupropion (OR 1.74; 95% CI, 1.41 to 2.14), and nicotine patch (OR 1.62; 95% CI, 1.32 to 1.99).³

Continue to: Further analysis of EAGLES

Beard et al⁴ used Bayes factor testing for additional analysis of EAGLES data to determine whether the data were insensitive to neuropsychiatric effects secondary to a lack of statistical power. In the psychiatric cohort, the varenicline and bupropion groups exhibited suggestive but not conclusive data that there was no increase in NPSAEs compared to placebo (Bayes factor 0.52 and 0.71, respectively).⁴

Another EAGLES analysis by Ayers et al⁵ evaluated participants with anxiety disorders (N = 712), including PTSD (N = 192), generalized anxiety disorder (GAD) (N = 243), and panic disorder (N = 277).Of those with PTSD who received varenicline, there were no statistically significant differences in CAR from Week 9 to Week 12 vs placebo.⁵ However, there was a significant difference in individuals with GAD (OR 4.53; 95% CI, 1.20 to 17.10), and panic disorder (OR 8.49; 95% CI, 1.57 to 45.78).⁵ In contrast to CAR from Week 9 to Week 12, 7-day point prevalence abstinence at Week 12 for participants with PTSD was significant (OR 4.04; 95% CI, 1.39 to 11.74) when comparing varenicline to placebo. Within the anxiety disorder cohort, there were no significant differences in moderate to severe NPSAE rates based on treatment group. Calculated risk differences comparing varenicline to placebo were: PTSD group -7.73 (95% CI, -21.95 to 6.49), GAD group 2.80 (95% CI, -6.63 to 12.23), and panic disorder group -0.18 (95% CI, -9.57 to 9.21).⁵

Other studies

Evins et al⁶ conducted a randomized controlled trial to evaluate the safety of varenicline maintenance therapy in patients with schizophrenia or bipolar disorder. To be deemed clinically stable, participants in this study needed to be taking a stable dose of an antipsychotic or mood-stabilizing agent(s) for ≥30 days, compared to the 3-month requirement of the EAGLES trial.^3,6 Participants received 12 weeks of open-label varenicline; those who achieved abstinence (N = 87) entered the relapse-prevention phase and were randomized to varenicline 1 mg twice a day or placebo for 40 weeks. Of those who entered relapse-prevention, 5 in the placebo group and 2 in the varenicline group were psychiatrically hospitalized (risk ratio 0.45; 95% CI, 0.04 to 2.9).⁶ These researchers concluded that varenicline maintenance therapy prolonged abstinence rates with no significant increase in neuropsychiatric events.⁶

Although treatment options for smoking cessation have advanced, individuals with SMI are still disproportionately affected by the negative outcomes of cigarette smoking. Current literature suggests that varenicline does not confer an appreciable risk of neuropsychiatric events in otherwise stable patients and is the preferred first-line treatment. However, there is a gap in understanding the impact of this medication on individuals with unstable psychiatric illness. Health care professionals should be encouraged to use varenicline with careful monitoring for appropriate patients with psychiatric disorders as a standard of care to help them quit smoking.

CASE CONTINUED

After consulting with the psychiatric pharmacist and discussing the risks and benefits of varenicline, Mr. T is started on the appropriate titration schedule (Table 1¹). A pharmacist provides varenicline education, including the possibility of psychiatric adverse effects, and tells Mr. T to report any worsening psychiatric symptoms. Mr. T is scheduled for frequent follow-up visits to monitor possible adverse effects and his tobacco use. He says he understands the potential adverse effects of varenicline and agrees to frequent follow-up appointments while taking it.

Related Resources

• Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic treatment in tobacco-dependent adults. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;202(2):e5-e31. doi:10.1164/rccm.202005.1982ST
• Cieslak K, Freudenreich O. 4 Ways to help your patients with schizophrenia quit smoking. Current Psychiatry. 2018; 17(2):28,33.

Drug Brand Names

Bupropion • Wellbutrin
Varenicline • Chantix

Mr. T, age 34, is a veteran who recently returned to civilian life. He presents to his local Veteran Affairs facility for transition of care. During active duty, he had been diagnosed with obstructive sleep apnea, tobacco use disorder, posttraumatic stress disorder (PTSD) secondary to combat exposure, and insomnia. Mr. T says he wants to quit smoking; currently, he smokes 2 packs of cigarettes per day. The primary care clinician notes that Mr. T has uncontrolled PTSD symptoms and poor sleep, and refers him for an outpatient mental health appointment.

At the mental health appointment 3 weeks later, Mr. T asks about medications to quit smoking, specifically varenicline (Table 1¹). Mr. T’s PTSD Checklist for DSM-5 score is 52, which indicates severe PTSD symptomatology. He says he sees shadowy figures in his periphery every day, and worries they are spying on him. His wife reports Mr. T has had these symptoms for most of their 10-year marriage but has never been treated for them. After a discussion with the outpatient team, Mr. T says he is willing to engage in exposure therapy for PTSD, but he does not want to take any medications other than varenicline for smoking cessation.

Cigarette smoke is a known carcinogen and risk factor for the development of cardiovascular and respiratory diseases and other comorbidities. People with severe mental illness (SMI) are 3 to 5 times more likely to smoke, and they often face multiple barriers to cessation, including low socioeconomic status and lack of support.² Even when patients with SMI are provided appropriate behavioral and pharmacologic interventions, they often require more frequent monitoring and counseling, receive a longer duration of drug therapy, and experience lower smoking cessation rates than the general population.²

Current guidelines recommend nicotine replacement therapy (NRT), bupropion, varenicline, and behavioral support as first-line therapies for smoking cessation in patients with and without SMI.² Evidence suggests that varenicline is more effective than other pharmacologic options; however, in 2009 a black-box warning was added to both varenicline and bupropion to highlight an increased risk of neuropsychiatric events in individuals with SMI.² This led some clinicians to hesitate to prescribe varenicline or bupropion to patients with psychiatric illness. However, in 2016, the EAGLES trial evaluated the safety of varenicline, bupropion, and NRT in smokers with and without psychiatric disorders, and based on the findings, the black-box warning was removed.² 

This article reviews the evidence regarding the use of varenicline and the risk of neuropsychiatric adverse events in patients with psychiatric illness. Table 2^3-6 provides a summary of each varenicline trial we discuss.

The EAGLES trial

EAGLES was a multicenter, multinational, randomized, double-blind, triple-dummy, placebo- and active-controlled trial of 8,144 individuals who received treatment for smoking cessation.³ The primary endpoint was the incidence of a composite measure of moderate to severe neuropsychiatric events (NPSAEs).³ Participants were split into psychiatric (N = 4,116) and nonpsychiatric (N = 4,028) cohorts and randomized into 4 treatment arms: varenicline 1 mg twice a day, bupropion 150 mg twice a day, nicotine patch 21 mg/d with taper, or placebo, all for 12 weeks with an additional 12 weeks of follow-up. All participants smoked ≥10 cigarettes per day. Individuals in the psychiatric cohort had to be psychiatrically stable (no exacerbations for 6 months and stable treatment for 3 months). Exclusionary diagnoses included psychotic disorders (except schizophrenia and schizoaffective disorder), dementia, substance use (except nicotine), and personality disorders (except borderline personality disorder).²

The rates of moderate to severe NPSAEs in the varenicline groups were 1.25% (95% CI, 0.60 to 1.90) in the nonpsychiatric cohort and 6.42% (95% CI, 4.91 to 7.93) in the psychiatric cohort.³ However, when comparing the varenicline group of the psychiatric cohort to the other arms of the psychiatric cohort, there were no differences (bupropion 6.62% [95% CI, 5.09 to 8.15], nicotine patch 5.20% [95% CI, 3.84 to 6.56], placebo 4.83% [95% CI, 3.51 to 6.16], respectively). The primary efficacy endpoint was continuous abstinence rates (CAR) for Week 9 through Week 12. In the psychiatric cohort, varenicline was superior compared to placebo (odds ratio [OR] 3.24; 95% CI, 2.56 to 4.11), bupropion (OR 1.74; 95% CI, 1.41 to 2.14), and nicotine patch (OR 1.62; 95% CI, 1.32 to 1.99).³

Continue to: Further analysis of EAGLES

Beard et al⁴ used Bayes factor testing for additional analysis of EAGLES data to determine whether the data were insensitive to neuropsychiatric effects secondary to a lack of statistical power. In the psychiatric cohort, the varenicline and bupropion groups exhibited suggestive but not conclusive data that there was no increase in NPSAEs compared to placebo (Bayes factor 0.52 and 0.71, respectively).⁴

Another EAGLES analysis by Ayers et al⁵ evaluated participants with anxiety disorders (N = 712), including PTSD (N = 192), generalized anxiety disorder (GAD) (N = 243), and panic disorder (N = 277).Of those with PTSD who received varenicline, there were no statistically significant differences in CAR from Week 9 to Week 12 vs placebo.⁵ However, there was a significant difference in individuals with GAD (OR 4.53; 95% CI, 1.20 to 17.10), and panic disorder (OR 8.49; 95% CI, 1.57 to 45.78).⁵ In contrast to CAR from Week 9 to Week 12, 7-day point prevalence abstinence at Week 12 for participants with PTSD was significant (OR 4.04; 95% CI, 1.39 to 11.74) when comparing varenicline to placebo. Within the anxiety disorder cohort, there were no significant differences in moderate to severe NPSAE rates based on treatment group. Calculated risk differences comparing varenicline to placebo were: PTSD group -7.73 (95% CI, -21.95 to 6.49), GAD group 2.80 (95% CI, -6.63 to 12.23), and panic disorder group -0.18 (95% CI, -9.57 to 9.21).⁵

Other studies

Evins et al⁶ conducted a randomized controlled trial to evaluate the safety of varenicline maintenance therapy in patients with schizophrenia or bipolar disorder. To be deemed clinically stable, participants in this study needed to be taking a stable dose of an antipsychotic or mood-stabilizing agent(s) for ≥30 days, compared to the 3-month requirement of the EAGLES trial.^3,6 Participants received 12 weeks of open-label varenicline; those who achieved abstinence (N = 87) entered the relapse-prevention phase and were randomized to varenicline 1 mg twice a day or placebo for 40 weeks. Of those who entered relapse-prevention, 5 in the placebo group and 2 in the varenicline group were psychiatrically hospitalized (risk ratio 0.45; 95% CI, 0.04 to 2.9).⁶ These researchers concluded that varenicline maintenance therapy prolonged abstinence rates with no significant increase in neuropsychiatric events.⁶

Although treatment options for smoking cessation have advanced, individuals with SMI are still disproportionately affected by the negative outcomes of cigarette smoking. Current literature suggests that varenicline does not confer an appreciable risk of neuropsychiatric events in otherwise stable patients and is the preferred first-line treatment. However, there is a gap in understanding the impact of this medication on individuals with unstable psychiatric illness. Health care professionals should be encouraged to use varenicline with careful monitoring for appropriate patients with psychiatric disorders as a standard of care to help them quit smoking.

CASE CONTINUED

After consulting with the psychiatric pharmacist and discussing the risks and benefits of varenicline, Mr. T is started on the appropriate titration schedule (Table 1¹). A pharmacist provides varenicline education, including the possibility of psychiatric adverse effects, and tells Mr. T to report any worsening psychiatric symptoms. Mr. T is scheduled for frequent follow-up visits to monitor possible adverse effects and his tobacco use. He says he understands the potential adverse effects of varenicline and agrees to frequent follow-up appointments while taking it.

Related Resources

• Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic treatment in tobacco-dependent adults. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;202(2):e5-e31. doi:10.1164/rccm.202005.1982ST
• Cieslak K, Freudenreich O. 4 Ways to help your patients with schizophrenia quit smoking. Current Psychiatry. 2018; 17(2):28,33.

Drug Brand Names

Bupropion • Wellbutrin
Varenicline • Chantix

Mr. T, age 34, is a veteran who recently returned to civilian life. He presents to his local Veteran Affairs facility for transition of care. During active duty, he had been diagnosed with obstructive sleep apnea, tobacco use disorder, posttraumatic stress disorder (PTSD) secondary to combat exposure, and insomnia. Mr. T says he wants to quit smoking; currently, he smokes 2 packs of cigarettes per day. The primary care clinician notes that Mr. T has uncontrolled PTSD symptoms and poor sleep, and refers him for an outpatient mental health appointment.

At the mental health appointment 3 weeks later, Mr. T asks about medications to quit smoking, specifically varenicline (Table 1¹). Mr. T’s PTSD Checklist for DSM-5 score is 52, which indicates severe PTSD symptomatology. He says he sees shadowy figures in his periphery every day, and worries they are spying on him. His wife reports Mr. T has had these symptoms for most of their 10-year marriage but has never been treated for them. After a discussion with the outpatient team, Mr. T says he is willing to engage in exposure therapy for PTSD, but he does not want to take any medications other than varenicline for smoking cessation.

Cigarette smoke is a known carcinogen and risk factor for the development of cardiovascular and respiratory diseases and other comorbidities. People with severe mental illness (SMI) are 3 to 5 times more likely to smoke, and they often face multiple barriers to cessation, including low socioeconomic status and lack of support.² Even when patients with SMI are provided appropriate behavioral and pharmacologic interventions, they often require more frequent monitoring and counseling, receive a longer duration of drug therapy, and experience lower smoking cessation rates than the general population.²

Current guidelines recommend nicotine replacement therapy (NRT), bupropion, varenicline, and behavioral support as first-line therapies for smoking cessation in patients with and without SMI.² Evidence suggests that varenicline is more effective than other pharmacologic options; however, in 2009 a black-box warning was added to both varenicline and bupropion to highlight an increased risk of neuropsychiatric events in individuals with SMI.² This led some clinicians to hesitate to prescribe varenicline or bupropion to patients with psychiatric illness. However, in 2016, the EAGLES trial evaluated the safety of varenicline, bupropion, and NRT in smokers with and without psychiatric disorders, and based on the findings, the black-box warning was removed.² 

This article reviews the evidence regarding the use of varenicline and the risk of neuropsychiatric adverse events in patients with psychiatric illness. Table 2^3-6 provides a summary of each varenicline trial we discuss.

The EAGLES trial

EAGLES was a multicenter, multinational, randomized, double-blind, triple-dummy, placebo- and active-controlled trial of 8,144 individuals who received treatment for smoking cessation.³ The primary endpoint was the incidence of a composite measure of moderate to severe neuropsychiatric events (NPSAEs).³ Participants were split into psychiatric (N = 4,116) and nonpsychiatric (N = 4,028) cohorts and randomized into 4 treatment arms: varenicline 1 mg twice a day, bupropion 150 mg twice a day, nicotine patch 21 mg/d with taper, or placebo, all for 12 weeks with an additional 12 weeks of follow-up. All participants smoked ≥10 cigarettes per day. Individuals in the psychiatric cohort had to be psychiatrically stable (no exacerbations for 6 months and stable treatment for 3 months). Exclusionary diagnoses included psychotic disorders (except schizophrenia and schizoaffective disorder), dementia, substance use (except nicotine), and personality disorders (except borderline personality disorder).²

The rates of moderate to severe NPSAEs in the varenicline groups were 1.25% (95% CI, 0.60 to 1.90) in the nonpsychiatric cohort and 6.42% (95% CI, 4.91 to 7.93) in the psychiatric cohort.³ However, when comparing the varenicline group of the psychiatric cohort to the other arms of the psychiatric cohort, there were no differences (bupropion 6.62% [95% CI, 5.09 to 8.15], nicotine patch 5.20% [95% CI, 3.84 to 6.56], placebo 4.83% [95% CI, 3.51 to 6.16], respectively). The primary efficacy endpoint was continuous abstinence rates (CAR) for Week 9 through Week 12. In the psychiatric cohort, varenicline was superior compared to placebo (odds ratio [OR] 3.24; 95% CI, 2.56 to 4.11), bupropion (OR 1.74; 95% CI, 1.41 to 2.14), and nicotine patch (OR 1.62; 95% CI, 1.32 to 1.99).³

Continue to: Further analysis of EAGLES

Beard et al⁴ used Bayes factor testing for additional analysis of EAGLES data to determine whether the data were insensitive to neuropsychiatric effects secondary to a lack of statistical power. In the psychiatric cohort, the varenicline and bupropion groups exhibited suggestive but not conclusive data that there was no increase in NPSAEs compared to placebo (Bayes factor 0.52 and 0.71, respectively).⁴

Another EAGLES analysis by Ayers et al⁵ evaluated participants with anxiety disorders (N = 712), including PTSD (N = 192), generalized anxiety disorder (GAD) (N = 243), and panic disorder (N = 277).Of those with PTSD who received varenicline, there were no statistically significant differences in CAR from Week 9 to Week 12 vs placebo.⁵ However, there was a significant difference in individuals with GAD (OR 4.53; 95% CI, 1.20 to 17.10), and panic disorder (OR 8.49; 95% CI, 1.57 to 45.78).⁵ In contrast to CAR from Week 9 to Week 12, 7-day point prevalence abstinence at Week 12 for participants with PTSD was significant (OR 4.04; 95% CI, 1.39 to 11.74) when comparing varenicline to placebo. Within the anxiety disorder cohort, there were no significant differences in moderate to severe NPSAE rates based on treatment group. Calculated risk differences comparing varenicline to placebo were: PTSD group -7.73 (95% CI, -21.95 to 6.49), GAD group 2.80 (95% CI, -6.63 to 12.23), and panic disorder group -0.18 (95% CI, -9.57 to 9.21).⁵

Other studies

Evins et al⁶ conducted a randomized controlled trial to evaluate the safety of varenicline maintenance therapy in patients with schizophrenia or bipolar disorder. To be deemed clinically stable, participants in this study needed to be taking a stable dose of an antipsychotic or mood-stabilizing agent(s) for ≥30 days, compared to the 3-month requirement of the EAGLES trial.^3,6 Participants received 12 weeks of open-label varenicline; those who achieved abstinence (N = 87) entered the relapse-prevention phase and were randomized to varenicline 1 mg twice a day or placebo for 40 weeks. Of those who entered relapse-prevention, 5 in the placebo group and 2 in the varenicline group were psychiatrically hospitalized (risk ratio 0.45; 95% CI, 0.04 to 2.9).⁶ These researchers concluded that varenicline maintenance therapy prolonged abstinence rates with no significant increase in neuropsychiatric events.⁶

Although treatment options for smoking cessation have advanced, individuals with SMI are still disproportionately affected by the negative outcomes of cigarette smoking. Current literature suggests that varenicline does not confer an appreciable risk of neuropsychiatric events in otherwise stable patients and is the preferred first-line treatment. However, there is a gap in understanding the impact of this medication on individuals with unstable psychiatric illness. Health care professionals should be encouraged to use varenicline with careful monitoring for appropriate patients with psychiatric disorders as a standard of care to help them quit smoking.

CASE CONTINUED

After consulting with the psychiatric pharmacist and discussing the risks and benefits of varenicline, Mr. T is started on the appropriate titration schedule (Table 1¹). A pharmacist provides varenicline education, including the possibility of psychiatric adverse effects, and tells Mr. T to report any worsening psychiatric symptoms. Mr. T is scheduled for frequent follow-up visits to monitor possible adverse effects and his tobacco use. He says he understands the potential adverse effects of varenicline and agrees to frequent follow-up appointments while taking it.

Related Resources

• Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic treatment in tobacco-dependent adults. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;202(2):e5-e31. doi:10.1164/rccm.202005.1982ST
• Cieslak K, Freudenreich O. 4 Ways to help your patients with schizophrenia quit smoking. Current Psychiatry. 2018; 17(2):28,33.

Drug Brand Names

Bupropion • Wellbutrin
Varenicline • Chantix

While our understanding of the mechanisms of psychosis continues to evolve beyond the dopamine hypothesis, the key role of dopamine in psychosis and its treatment has not faded.¹ Over time, the dopamine hypothesis of schizophrenia has evolved from focusing on dopamine hyperactivity to specifying the regional abnormalities in the brain with subcortical hyperdopaminergia and prefrontal hypodopaminergia.² Despite this divergence in dopaminergic function, antipsychotic medications that block dopamine D2 receptors (D2R) remain central to treating psychotic symptoms and preventing relapse.^3,4 Notably, antipsychotics block both presynaptic and postsynaptic receptors affecting the regulation of dopamine synthesis and release in the brain.^5,6

Chronic dopamine D2R blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. In this article, we discuss these changes, and steps clinicians can take to minimize their occurrence.

Dopamine D2R: A primer

There are 5 types of dopamine receptors, numbered D1 through D5, but there are only 2 families of dopamine receptors: the D1 family (D1 and D5), and the D2 family (D2, D3, and D4). All dopamine receptors are G protein–coupled, but the D2 family of receptors generally increases protein kinase A (PKA) as the second messenger, whereas the D1 family increases cyclic adenosine monophosphate (cAMP) as the second messenger.⁵ There are 2 distinct variants of the D2R of 2 different lengths made from the same gene (DRD2) via posttranslational modification. The long isoform of D2R (D2_L) has an additional 29 amino acids compared to the short isoform (D2_S).⁷ Additional evidence points to a third splice variant called D2_Longer that arises from aberrant RNA splicing and contains 2 more amino acids than D2_L; its relevance is not known.⁸

The D2_L isoform is the primary postsynaptic receptor, expressed more in the striatum and nucleus accumbens (NAc) targeted by dopaminergic afferents. The D2_S isoform, however, is predominantly presynaptic, more densely expressed on cell bodies and projection axons of the dopaminergic neurons of the midbrain and hypothalamus.⁹ Each isoform contributes differentially to the therapeutic and adverse effects of antipsychotics, and evidence from animal studies suggests that D2_L is the main variant responsible for drug-induced parkinsonism.¹⁰ The D2_S acts as the principal autoreceptor for the dopaminergic system.^5,11,12

Autoreceptors regulate dopamine transmission. Dopamine itself and D2R agonists are reported to have higher affinity and potency with D2_S. Activation of these autoreceptors is a negative feedback mechanism that decreases dopamine release. Similarly, when they are blocked (such as with use of an antipsychotic), there is an increase in dopamine release. Additionally, these autoreceptors modulate several key processes:

• neuronal firing rate by activating potassium conductance
• dopamine synthesis by downregulating the expression of tyrosine hydroxylase (TH) enzyme (the rate-limiting step)
• exocytotic release of dopamine and other neurotransmitters
• dopamine reuptake via increasing the activity of the dopamine transporter (DAT).¹²

Consequences of antipsychotic D2R blockade

Most antipsychotics begin to produce a therapeutic antipsychotic effect at 65% to 75% occupancy of the D2Rs.³ This level also produces an optimal balance between clinical efficacy and a lower incidence of adverse effects.³ A higher D2R occupancy by both first-generation (FGA) and second-generation (SGA) pure antagonist antipsychotics can lead to parkinsonism.

Parkinsonism is associated with the subsequent appearance of one of the most distressing consequences of long-term antipsychotic treatment, tardive dyskinesia (TD).¹³ TD is an iatrogenic, usually late-onset syndrome consisting of persistent, involuntary, and repetitive movements. It classically involves the highly innervated striated muscles of the tongue, mouth, face, and fingers, though it can also involve the trunk and extremities.¹⁴ It occurs secondary to chronic exposure to dopamine receptor–blocking agents, including dopaminergic antiemetics.¹⁵ The prevalence of TD is higher in patients treated long-term with FGAs (30.0% to 32.4%) than in those treated with SGAs (13.1% to 20.7%) due to serotonin 5HT2A blockade that results in increased dopamine release in the basal ganglia.¹⁶

Continue to: Dopamine supersenstivity psychosis...

Dopamine supersensitivity psychosis (DSP) is a term that describes the clinical iatrogenic phenomenon that might be observed with long-term antipsychotic treatment. DSP is suggested to be strongly associated with treatment failure/resistance in schizophrenia.^17,18 Manifestations of DSP include development of antipsychotic drug tolerance that undermines treatment efficacy, rebound psychosis during or after treatment discontinuation, and the presence of TD. Like TD, it may be reversed temporarily by increasing the dose of the antipsychotic.¹⁸

DSP and (more extensively) TD are commonly hypothesized to result from the postsynaptic dopamine receptor supersensitivity that develops because of chronic D2Rs blockade by antipsychotics. Neostriatal dopamine receptor supersensitivity is believed to lead to TD, while mesolimbic supersensitivity leads to DSP.¹⁹ Supersensitivity has traditionally been believed to be due to upregulation of postsynaptic D2R number and sensitivity.^20,21 However, both TD and DSP are more likely a consequence of a host of compensatory neurobiological adaptations across the synapse that include:

• postsynaptic increase in the number of D2Rs that amplifies the dopamine signal
• an increased number of synapses, dendritic spines, and perforated synapses (seen in animal models), all of which lead to a potentiated dopamine signal
• presynaptic changes with higher levels of dopamine released into the synapse via an increase in quantal size as postsynaptic D2Rs blockade results in more dopamine becoming available in the synapse for recycling via the dopamine transporter
• increased dopamine turnover due to presynaptic D2_S autoreceptor blockade.²²

So if giving a D2R blocking agent for a long time increases the dopamine signal, at least in some patients, what can the clinician do to treat the psychosis, and not cause changes in the brain that could lead to TD or DSP?

Partial agonist antipsychotics and biased agonism of D2Rs

One approach to try to avoid the compensatory changes to dopamine blockade might be to use a D2R partial agonist.^18,23 For example, aripiprazole is a partial agonist at the D2R commonly used to manage schizophrenia and bipolar disorder. It possesses greater affinity at the D2R compared with the serotonin 2A (5-hydroxytryptamine, 5HT2A) serotonin receptor. Unlike full antagonists, aripiprazole requires exceptionally high D2 receptor occupancy (approximately 90%) to be at a clinically effective antipsychotic dose.^24,25 This is a general requirement for all D2R partial agonists.²⁶

A partial agonist generally has to possess greater affinity to the receptor than the neurotransmitter with which it is competing. Aripiprazole has more than twice the affinity to D2R than dopamine. Other partial agonists have similarly high, or higher, D2R affinity. Effective antipsychotic partial agonists stimulate the D2Rs at approximately 30% ± 10% the maximal signal achieved with dopamine. This is essentially equivalent to having approximately 70% receptor occupancy with a full antagonist, except it is built into how the molecule works. Having this low-grade partial activation of D2Rs creates multiple receptor-mediated actions:

• reduction of cAMP accumulation
• antagonism to guanosine 5’-0-(3-thio) triphosphate (GTPgamma S) binding with relatively less recruitment of beta-arrestin 2 (these diverging effects on G protein are the definition of biased agonism)
• antagonism of G protein activation of K⁺ channels (GIRK) activity
• agonism for the inhibition of TH.

Continue to: Additionally, aripiprazole was found...

Additionally, aripiprazole was found to be associated with a lesser increase in dopamine turnover than full antagonist antipsychotics (Figure²⁷) and decreased DAT binding density in NAc and the ventral tegmental area (VTA). The distinctive pharmacologic profile and biased agonism of this drug could be attributed to its ability to activate presynaptic D2 autoreceptors, which, as previously mentioned, regulate dopamine release via negative feedback mechanism.^5,25 Cariprazine, another D2R partial agonist, has similar doubling of dopamine turnover.²⁸

Activation of presynaptic D2_S receptors ultimately leads to decreased dopamine synthesis and release, which combats or prevents the brain adaptations regarding dopamine supersensitivity and D2Rs upregulation. While TD can still occur occasionally with aripiprazole or other partial agonists,^29,30 animal studies show that administration of methamphetamine significantly lowers locomotor response and the density of striatal D2Rs in a group treated with aripiprazole compared to a group treated with haloperidol.³¹ Aripiprazole also improved the supersensitivity parameters induced by chronic treatment with haloperidol, which suggests that it is associated with reduced dopamine supersensitivity.³¹ Similarly, in human studies, partial agonists appear to have a lower rate of parkinsonism and TD.^32,33 One study reported that aripiprazole was associated with a significant improvement of TD in more than 50% of patients after 24 weeks of treatment.³⁴

Lumateperone’s unique pharmacologic profile

Lumateperone is a newer antipsychotic that was FDA-approved in December 2019 for the treatment of adults with schizophrenia³⁵ and more recently for the treatment of bipolar depression.³⁶ It possesses a unique combination of pharmacologic properties; it is a postsynaptic D2R antagonist and a presynaptic D2R partial agonist.²⁷

Interestingly, lumateperone has regional selectivity. It increases dopamine release in the medial prefrontal cortex (where D2R is rare) but not in the nigrostriatal pathways.^27,37 It does not increase TH phosphorylation (which would increase dopamine concentration) or dopamine turnover in the striatum (Figure²⁷). In a preclinical functional activity assay of lumateperone, the lack of change of dopamine turnover with lumateperone resembles placebo and is even less than that observed with aripiprazole (Figure²⁷). This effect is consistent with partial agonism at the presynaptic D2_S, where the stimulation of that receptor prevents the concomitant increase in dopamine synthesis and release that occurs when that receptor is blocked.

It is believed that the lack of increase in dopamine turnover is one of the reasons that lumateperone postsynaptic D2R occupancy is exceptionally low at clinically effective doses. In a positron emission tomography study analyzing posttreatment scans after approximately 2 weeks of a 60 mg/d dose, the mean peak striatal D2R occupancy was approximately 40%,³⁸ which is remarkably lower than the 65% to 75% blockade needed for purely antagonist D2R antipsychotics.³ This low receptor occupancy appears to mediate the low incidence of parkinsonism and prolactin release seen with lumateperone.

Continue to: Take-home points

Take-home points

Adaptive upregulation of dopamine neuro­transmission underlies acute adverse effects such as parkinsonism and is also key for delayed consequences such as TD, and possibly the development of treatment resistance. Adaptive upregulation results from an increase in postsynaptic dopamine receptors, numbers of synapses, and dopamine release. The latter has been demonstrated to be greatest with full antagonists, less with partial agonists, and not present with lumateperone, which is a postsynaptic antagonist but a presynaptic partial agonist (Figure²⁷). Reducing adaptive upregulation can reduce both acute and long-term consequences of dopamine blockade. Early use of agents that minimize these adaptive changes, such as a postsynaptic partial agonist (aripiprazole, brexpiprazole, or cariprazine) or a presynaptic partial agonist (lumateperone), appears to be a reasonable clinical option.

Bottom Line

Chronic dopamine D2 receptor blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. The most severe of these are tardive dyskinesia (TD) and dopamine supersensitivity psychosis (DSP). The use of agents that mitigate these changes, such as the partial D2 agonists aripiprazole, brexpiprazole, and cariprazine and the postsynaptic antagonist/presynaptic partial agonist lumateperone, can potentially reduce these adaptive changes and reduce the likelihood of TD and DSP.

Related Resources

• Citrome L. Aripiprazole, brexpiprazole, and cariprazine: not all the same. Current Psychiatry. 2018;17(4):24-33,43.
• Meyer JM. Lumateperone for schizophrenia. Current Psychiatry. 2020;19(2):33-39.

Drug Brand Names

Aripiprazole • Abilify
Brexpiprazole • Rexulti
Cariprazine • Vraylar
Haloperidol • Haldol
Lumateperone • Caplyta
Methamphetamine • Desoxyn
Risperidone • Risperdal

While our understanding of the mechanisms of psychosis continues to evolve beyond the dopamine hypothesis, the key role of dopamine in psychosis and its treatment has not faded.¹ Over time, the dopamine hypothesis of schizophrenia has evolved from focusing on dopamine hyperactivity to specifying the regional abnormalities in the brain with subcortical hyperdopaminergia and prefrontal hypodopaminergia.² Despite this divergence in dopaminergic function, antipsychotic medications that block dopamine D2 receptors (D2R) remain central to treating psychotic symptoms and preventing relapse.^3,4 Notably, antipsychotics block both presynaptic and postsynaptic receptors affecting the regulation of dopamine synthesis and release in the brain.^5,6

Chronic dopamine D2R blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. In this article, we discuss these changes, and steps clinicians can take to minimize their occurrence.

Dopamine D2R: A primer

There are 5 types of dopamine receptors, numbered D1 through D5, but there are only 2 families of dopamine receptors: the D1 family (D1 and D5), and the D2 family (D2, D3, and D4). All dopamine receptors are G protein–coupled, but the D2 family of receptors generally increases protein kinase A (PKA) as the second messenger, whereas the D1 family increases cyclic adenosine monophosphate (cAMP) as the second messenger.⁵ There are 2 distinct variants of the D2R of 2 different lengths made from the same gene (DRD2) via posttranslational modification. The long isoform of D2R (D2_L) has an additional 29 amino acids compared to the short isoform (D2_S).⁷ Additional evidence points to a third splice variant called D2_Longer that arises from aberrant RNA splicing and contains 2 more amino acids than D2_L; its relevance is not known.⁸

The D2_L isoform is the primary postsynaptic receptor, expressed more in the striatum and nucleus accumbens (NAc) targeted by dopaminergic afferents. The D2_S isoform, however, is predominantly presynaptic, more densely expressed on cell bodies and projection axons of the dopaminergic neurons of the midbrain and hypothalamus.⁹ Each isoform contributes differentially to the therapeutic and adverse effects of antipsychotics, and evidence from animal studies suggests that D2_L is the main variant responsible for drug-induced parkinsonism.¹⁰ The D2_S acts as the principal autoreceptor for the dopaminergic system.^5,11,12

Autoreceptors regulate dopamine transmission. Dopamine itself and D2R agonists are reported to have higher affinity and potency with D2_S. Activation of these autoreceptors is a negative feedback mechanism that decreases dopamine release. Similarly, when they are blocked (such as with use of an antipsychotic), there is an increase in dopamine release. Additionally, these autoreceptors modulate several key processes:

• neuronal firing rate by activating potassium conductance
• dopamine synthesis by downregulating the expression of tyrosine hydroxylase (TH) enzyme (the rate-limiting step)
• exocytotic release of dopamine and other neurotransmitters
• dopamine reuptake via increasing the activity of the dopamine transporter (DAT).¹²

Consequences of antipsychotic D2R blockade

Most antipsychotics begin to produce a therapeutic antipsychotic effect at 65% to 75% occupancy of the D2Rs.³ This level also produces an optimal balance between clinical efficacy and a lower incidence of adverse effects.³ A higher D2R occupancy by both first-generation (FGA) and second-generation (SGA) pure antagonist antipsychotics can lead to parkinsonism.

Parkinsonism is associated with the subsequent appearance of one of the most distressing consequences of long-term antipsychotic treatment, tardive dyskinesia (TD).¹³ TD is an iatrogenic, usually late-onset syndrome consisting of persistent, involuntary, and repetitive movements. It classically involves the highly innervated striated muscles of the tongue, mouth, face, and fingers, though it can also involve the trunk and extremities.¹⁴ It occurs secondary to chronic exposure to dopamine receptor–blocking agents, including dopaminergic antiemetics.¹⁵ The prevalence of TD is higher in patients treated long-term with FGAs (30.0% to 32.4%) than in those treated with SGAs (13.1% to 20.7%) due to serotonin 5HT2A blockade that results in increased dopamine release in the basal ganglia.¹⁶

Continue to: Dopamine supersenstivity psychosis...

Dopamine supersensitivity psychosis (DSP) is a term that describes the clinical iatrogenic phenomenon that might be observed with long-term antipsychotic treatment. DSP is suggested to be strongly associated with treatment failure/resistance in schizophrenia.^17,18 Manifestations of DSP include development of antipsychotic drug tolerance that undermines treatment efficacy, rebound psychosis during or after treatment discontinuation, and the presence of TD. Like TD, it may be reversed temporarily by increasing the dose of the antipsychotic.¹⁸

DSP and (more extensively) TD are commonly hypothesized to result from the postsynaptic dopamine receptor supersensitivity that develops because of chronic D2Rs blockade by antipsychotics. Neostriatal dopamine receptor supersensitivity is believed to lead to TD, while mesolimbic supersensitivity leads to DSP.¹⁹ Supersensitivity has traditionally been believed to be due to upregulation of postsynaptic D2R number and sensitivity.^20,21 However, both TD and DSP are more likely a consequence of a host of compensatory neurobiological adaptations across the synapse that include:

• postsynaptic increase in the number of D2Rs that amplifies the dopamine signal
• an increased number of synapses, dendritic spines, and perforated synapses (seen in animal models), all of which lead to a potentiated dopamine signal
• presynaptic changes with higher levels of dopamine released into the synapse via an increase in quantal size as postsynaptic D2Rs blockade results in more dopamine becoming available in the synapse for recycling via the dopamine transporter
• increased dopamine turnover due to presynaptic D2_S autoreceptor blockade.²²

So if giving a D2R blocking agent for a long time increases the dopamine signal, at least in some patients, what can the clinician do to treat the psychosis, and not cause changes in the brain that could lead to TD or DSP?

Partial agonist antipsychotics and biased agonism of D2Rs

One approach to try to avoid the compensatory changes to dopamine blockade might be to use a D2R partial agonist.^18,23 For example, aripiprazole is a partial agonist at the D2R commonly used to manage schizophrenia and bipolar disorder. It possesses greater affinity at the D2R compared with the serotonin 2A (5-hydroxytryptamine, 5HT2A) serotonin receptor. Unlike full antagonists, aripiprazole requires exceptionally high D2 receptor occupancy (approximately 90%) to be at a clinically effective antipsychotic dose.^24,25 This is a general requirement for all D2R partial agonists.²⁶

A partial agonist generally has to possess greater affinity to the receptor than the neurotransmitter with which it is competing. Aripiprazole has more than twice the affinity to D2R than dopamine. Other partial agonists have similarly high, or higher, D2R affinity. Effective antipsychotic partial agonists stimulate the D2Rs at approximately 30% ± 10% the maximal signal achieved with dopamine. This is essentially equivalent to having approximately 70% receptor occupancy with a full antagonist, except it is built into how the molecule works. Having this low-grade partial activation of D2Rs creates multiple receptor-mediated actions:

• reduction of cAMP accumulation
• antagonism to guanosine 5’-0-(3-thio) triphosphate (GTPgamma S) binding with relatively less recruitment of beta-arrestin 2 (these diverging effects on G protein are the definition of biased agonism)
• antagonism of G protein activation of K⁺ channels (GIRK) activity
• agonism for the inhibition of TH.

Continue to: Additionally, aripiprazole was found...

Additionally, aripiprazole was found to be associated with a lesser increase in dopamine turnover than full antagonist antipsychotics (Figure²⁷) and decreased DAT binding density in NAc and the ventral tegmental area (VTA). The distinctive pharmacologic profile and biased agonism of this drug could be attributed to its ability to activate presynaptic D2 autoreceptors, which, as previously mentioned, regulate dopamine release via negative feedback mechanism.^5,25 Cariprazine, another D2R partial agonist, has similar doubling of dopamine turnover.²⁸

Activation of presynaptic D2_S receptors ultimately leads to decreased dopamine synthesis and release, which combats or prevents the brain adaptations regarding dopamine supersensitivity and D2Rs upregulation. While TD can still occur occasionally with aripiprazole or other partial agonists,^29,30 animal studies show that administration of methamphetamine significantly lowers locomotor response and the density of striatal D2Rs in a group treated with aripiprazole compared to a group treated with haloperidol.³¹ Aripiprazole also improved the supersensitivity parameters induced by chronic treatment with haloperidol, which suggests that it is associated with reduced dopamine supersensitivity.³¹ Similarly, in human studies, partial agonists appear to have a lower rate of parkinsonism and TD.^32,33 One study reported that aripiprazole was associated with a significant improvement of TD in more than 50% of patients after 24 weeks of treatment.³⁴

Lumateperone’s unique pharmacologic profile

Lumateperone is a newer antipsychotic that was FDA-approved in December 2019 for the treatment of adults with schizophrenia³⁵ and more recently for the treatment of bipolar depression.³⁶ It possesses a unique combination of pharmacologic properties; it is a postsynaptic D2R antagonist and a presynaptic D2R partial agonist.²⁷

Interestingly, lumateperone has regional selectivity. It increases dopamine release in the medial prefrontal cortex (where D2R is rare) but not in the nigrostriatal pathways.^27,37 It does not increase TH phosphorylation (which would increase dopamine concentration) or dopamine turnover in the striatum (Figure²⁷). In a preclinical functional activity assay of lumateperone, the lack of change of dopamine turnover with lumateperone resembles placebo and is even less than that observed with aripiprazole (Figure²⁷). This effect is consistent with partial agonism at the presynaptic D2_S, where the stimulation of that receptor prevents the concomitant increase in dopamine synthesis and release that occurs when that receptor is blocked.

It is believed that the lack of increase in dopamine turnover is one of the reasons that lumateperone postsynaptic D2R occupancy is exceptionally low at clinically effective doses. In a positron emission tomography study analyzing posttreatment scans after approximately 2 weeks of a 60 mg/d dose, the mean peak striatal D2R occupancy was approximately 40%,³⁸ which is remarkably lower than the 65% to 75% blockade needed for purely antagonist D2R antipsychotics.³ This low receptor occupancy appears to mediate the low incidence of parkinsonism and prolactin release seen with lumateperone.

Continue to: Take-home points

Take-home points

Adaptive upregulation of dopamine neuro­transmission underlies acute adverse effects such as parkinsonism and is also key for delayed consequences such as TD, and possibly the development of treatment resistance. Adaptive upregulation results from an increase in postsynaptic dopamine receptors, numbers of synapses, and dopamine release. The latter has been demonstrated to be greatest with full antagonists, less with partial agonists, and not present with lumateperone, which is a postsynaptic antagonist but a presynaptic partial agonist (Figure²⁷). Reducing adaptive upregulation can reduce both acute and long-term consequences of dopamine blockade. Early use of agents that minimize these adaptive changes, such as a postsynaptic partial agonist (aripiprazole, brexpiprazole, or cariprazine) or a presynaptic partial agonist (lumateperone), appears to be a reasonable clinical option.

Bottom Line

Chronic dopamine D2 receptor blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. The most severe of these are tardive dyskinesia (TD) and dopamine supersensitivity psychosis (DSP). The use of agents that mitigate these changes, such as the partial D2 agonists aripiprazole, brexpiprazole, and cariprazine and the postsynaptic antagonist/presynaptic partial agonist lumateperone, can potentially reduce these adaptive changes and reduce the likelihood of TD and DSP.

Related Resources

• Citrome L. Aripiprazole, brexpiprazole, and cariprazine: not all the same. Current Psychiatry. 2018;17(4):24-33,43.
• Meyer JM. Lumateperone for schizophrenia. Current Psychiatry. 2020;19(2):33-39.

Drug Brand Names

Aripiprazole • Abilify
Brexpiprazole • Rexulti
Cariprazine • Vraylar
Haloperidol • Haldol
Lumateperone • Caplyta
Methamphetamine • Desoxyn
Risperidone • Risperdal

While our understanding of the mechanisms of psychosis continues to evolve beyond the dopamine hypothesis, the key role of dopamine in psychosis and its treatment has not faded.¹ Over time, the dopamine hypothesis of schizophrenia has evolved from focusing on dopamine hyperactivity to specifying the regional abnormalities in the brain with subcortical hyperdopaminergia and prefrontal hypodopaminergia.² Despite this divergence in dopaminergic function, antipsychotic medications that block dopamine D2 receptors (D2R) remain central to treating psychotic symptoms and preventing relapse.^3,4 Notably, antipsychotics block both presynaptic and postsynaptic receptors affecting the regulation of dopamine synthesis and release in the brain.^5,6

Chronic dopamine D2R blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. In this article, we discuss these changes, and steps clinicians can take to minimize their occurrence.

Dopamine D2R: A primer

There are 5 types of dopamine receptors, numbered D1 through D5, but there are only 2 families of dopamine receptors: the D1 family (D1 and D5), and the D2 family (D2, D3, and D4). All dopamine receptors are G protein–coupled, but the D2 family of receptors generally increases protein kinase A (PKA) as the second messenger, whereas the D1 family increases cyclic adenosine monophosphate (cAMP) as the second messenger.⁵ There are 2 distinct variants of the D2R of 2 different lengths made from the same gene (DRD2) via posttranslational modification. The long isoform of D2R (D2_L) has an additional 29 amino acids compared to the short isoform (D2_S).⁷ Additional evidence points to a third splice variant called D2_Longer that arises from aberrant RNA splicing and contains 2 more amino acids than D2_L; its relevance is not known.⁸

The D2_L isoform is the primary postsynaptic receptor, expressed more in the striatum and nucleus accumbens (NAc) targeted by dopaminergic afferents. The D2_S isoform, however, is predominantly presynaptic, more densely expressed on cell bodies and projection axons of the dopaminergic neurons of the midbrain and hypothalamus.⁹ Each isoform contributes differentially to the therapeutic and adverse effects of antipsychotics, and evidence from animal studies suggests that D2_L is the main variant responsible for drug-induced parkinsonism.¹⁰ The D2_S acts as the principal autoreceptor for the dopaminergic system.^5,11,12

Autoreceptors regulate dopamine transmission. Dopamine itself and D2R agonists are reported to have higher affinity and potency with D2_S. Activation of these autoreceptors is a negative feedback mechanism that decreases dopamine release. Similarly, when they are blocked (such as with use of an antipsychotic), there is an increase in dopamine release. Additionally, these autoreceptors modulate several key processes:

• neuronal firing rate by activating potassium conductance
• dopamine synthesis by downregulating the expression of tyrosine hydroxylase (TH) enzyme (the rate-limiting step)
• exocytotic release of dopamine and other neurotransmitters
• dopamine reuptake via increasing the activity of the dopamine transporter (DAT).¹²

Consequences of antipsychotic D2R blockade

Most antipsychotics begin to produce a therapeutic antipsychotic effect at 65% to 75% occupancy of the D2Rs.³ This level also produces an optimal balance between clinical efficacy and a lower incidence of adverse effects.³ A higher D2R occupancy by both first-generation (FGA) and second-generation (SGA) pure antagonist antipsychotics can lead to parkinsonism.

Parkinsonism is associated with the subsequent appearance of one of the most distressing consequences of long-term antipsychotic treatment, tardive dyskinesia (TD).¹³ TD is an iatrogenic, usually late-onset syndrome consisting of persistent, involuntary, and repetitive movements. It classically involves the highly innervated striated muscles of the tongue, mouth, face, and fingers, though it can also involve the trunk and extremities.¹⁴ It occurs secondary to chronic exposure to dopamine receptor–blocking agents, including dopaminergic antiemetics.¹⁵ The prevalence of TD is higher in patients treated long-term with FGAs (30.0% to 32.4%) than in those treated with SGAs (13.1% to 20.7%) due to serotonin 5HT2A blockade that results in increased dopamine release in the basal ganglia.¹⁶

Continue to: Dopamine supersenstivity psychosis...

Dopamine supersensitivity psychosis (DSP) is a term that describes the clinical iatrogenic phenomenon that might be observed with long-term antipsychotic treatment. DSP is suggested to be strongly associated with treatment failure/resistance in schizophrenia.^17,18 Manifestations of DSP include development of antipsychotic drug tolerance that undermines treatment efficacy, rebound psychosis during or after treatment discontinuation, and the presence of TD. Like TD, it may be reversed temporarily by increasing the dose of the antipsychotic.¹⁸

DSP and (more extensively) TD are commonly hypothesized to result from the postsynaptic dopamine receptor supersensitivity that develops because of chronic D2Rs blockade by antipsychotics. Neostriatal dopamine receptor supersensitivity is believed to lead to TD, while mesolimbic supersensitivity leads to DSP.¹⁹ Supersensitivity has traditionally been believed to be due to upregulation of postsynaptic D2R number and sensitivity.^20,21 However, both TD and DSP are more likely a consequence of a host of compensatory neurobiological adaptations across the synapse that include:

• postsynaptic increase in the number of D2Rs that amplifies the dopamine signal
• an increased number of synapses, dendritic spines, and perforated synapses (seen in animal models), all of which lead to a potentiated dopamine signal
• presynaptic changes with higher levels of dopamine released into the synapse via an increase in quantal size as postsynaptic D2Rs blockade results in more dopamine becoming available in the synapse for recycling via the dopamine transporter
• increased dopamine turnover due to presynaptic D2_S autoreceptor blockade.²²

So if giving a D2R blocking agent for a long time increases the dopamine signal, at least in some patients, what can the clinician do to treat the psychosis, and not cause changes in the brain that could lead to TD or DSP?

Partial agonist antipsychotics and biased agonism of D2Rs

One approach to try to avoid the compensatory changes to dopamine blockade might be to use a D2R partial agonist.^18,23 For example, aripiprazole is a partial agonist at the D2R commonly used to manage schizophrenia and bipolar disorder. It possesses greater affinity at the D2R compared with the serotonin 2A (5-hydroxytryptamine, 5HT2A) serotonin receptor. Unlike full antagonists, aripiprazole requires exceptionally high D2 receptor occupancy (approximately 90%) to be at a clinically effective antipsychotic dose.^24,25 This is a general requirement for all D2R partial agonists.²⁶

A partial agonist generally has to possess greater affinity to the receptor than the neurotransmitter with which it is competing. Aripiprazole has more than twice the affinity to D2R than dopamine. Other partial agonists have similarly high, or higher, D2R affinity. Effective antipsychotic partial agonists stimulate the D2Rs at approximately 30% ± 10% the maximal signal achieved with dopamine. This is essentially equivalent to having approximately 70% receptor occupancy with a full antagonist, except it is built into how the molecule works. Having this low-grade partial activation of D2Rs creates multiple receptor-mediated actions:

• reduction of cAMP accumulation
• antagonism to guanosine 5’-0-(3-thio) triphosphate (GTPgamma S) binding with relatively less recruitment of beta-arrestin 2 (these diverging effects on G protein are the definition of biased agonism)
• antagonism of G protein activation of K⁺ channels (GIRK) activity
• agonism for the inhibition of TH.

Continue to: Additionally, aripiprazole was found...

Additionally, aripiprazole was found to be associated with a lesser increase in dopamine turnover than full antagonist antipsychotics (Figure²⁷) and decreased DAT binding density in NAc and the ventral tegmental area (VTA). The distinctive pharmacologic profile and biased agonism of this drug could be attributed to its ability to activate presynaptic D2 autoreceptors, which, as previously mentioned, regulate dopamine release via negative feedback mechanism.^5,25 Cariprazine, another D2R partial agonist, has similar doubling of dopamine turnover.²⁸

Activation of presynaptic D2_S receptors ultimately leads to decreased dopamine synthesis and release, which combats or prevents the brain adaptations regarding dopamine supersensitivity and D2Rs upregulation. While TD can still occur occasionally with aripiprazole or other partial agonists,^29,30 animal studies show that administration of methamphetamine significantly lowers locomotor response and the density of striatal D2Rs in a group treated with aripiprazole compared to a group treated with haloperidol.³¹ Aripiprazole also improved the supersensitivity parameters induced by chronic treatment with haloperidol, which suggests that it is associated with reduced dopamine supersensitivity.³¹ Similarly, in human studies, partial agonists appear to have a lower rate of parkinsonism and TD.^32,33 One study reported that aripiprazole was associated with a significant improvement of TD in more than 50% of patients after 24 weeks of treatment.³⁴

Lumateperone’s unique pharmacologic profile

Lumateperone is a newer antipsychotic that was FDA-approved in December 2019 for the treatment of adults with schizophrenia³⁵ and more recently for the treatment of bipolar depression.³⁶ It possesses a unique combination of pharmacologic properties; it is a postsynaptic D2R antagonist and a presynaptic D2R partial agonist.²⁷

Interestingly, lumateperone has regional selectivity. It increases dopamine release in the medial prefrontal cortex (where D2R is rare) but not in the nigrostriatal pathways.^27,37 It does not increase TH phosphorylation (which would increase dopamine concentration) or dopamine turnover in the striatum (Figure²⁷). In a preclinical functional activity assay of lumateperone, the lack of change of dopamine turnover with lumateperone resembles placebo and is even less than that observed with aripiprazole (Figure²⁷). This effect is consistent with partial agonism at the presynaptic D2_S, where the stimulation of that receptor prevents the concomitant increase in dopamine synthesis and release that occurs when that receptor is blocked.

It is believed that the lack of increase in dopamine turnover is one of the reasons that lumateperone postsynaptic D2R occupancy is exceptionally low at clinically effective doses. In a positron emission tomography study analyzing posttreatment scans after approximately 2 weeks of a 60 mg/d dose, the mean peak striatal D2R occupancy was approximately 40%,³⁸ which is remarkably lower than the 65% to 75% blockade needed for purely antagonist D2R antipsychotics.³ This low receptor occupancy appears to mediate the low incidence of parkinsonism and prolactin release seen with lumateperone.

Continue to: Take-home points

Take-home points

Adaptive upregulation of dopamine neuro­transmission underlies acute adverse effects such as parkinsonism and is also key for delayed consequences such as TD, and possibly the development of treatment resistance. Adaptive upregulation results from an increase in postsynaptic dopamine receptors, numbers of synapses, and dopamine release. The latter has been demonstrated to be greatest with full antagonists, less with partial agonists, and not present with lumateperone, which is a postsynaptic antagonist but a presynaptic partial agonist (Figure²⁷). Reducing adaptive upregulation can reduce both acute and long-term consequences of dopamine blockade. Early use of agents that minimize these adaptive changes, such as a postsynaptic partial agonist (aripiprazole, brexpiprazole, or cariprazine) or a presynaptic partial agonist (lumateperone), appears to be a reasonable clinical option.

Bottom Line

Chronic dopamine D2 receptor blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. The most severe of these are tardive dyskinesia (TD) and dopamine supersensitivity psychosis (DSP). The use of agents that mitigate these changes, such as the partial D2 agonists aripiprazole, brexpiprazole, and cariprazine and the postsynaptic antagonist/presynaptic partial agonist lumateperone, can potentially reduce these adaptive changes and reduce the likelihood of TD and DSP.

Related Resources

• Citrome L. Aripiprazole, brexpiprazole, and cariprazine: not all the same. Current Psychiatry. 2018;17(4):24-33,43.
• Meyer JM. Lumateperone for schizophrenia. Current Psychiatry. 2020;19(2):33-39.

Drug Brand Names

Aripiprazole • Abilify
Brexpiprazole • Rexulti
Cariprazine • Vraylar
Haloperidol • Haldol
Lumateperone • Caplyta
Methamphetamine • Desoxyn
Risperidone • Risperdal

Termination of pregnancy for medical reasons (TFMR) occurs when a pregnancy is ended due to medical complications that threaten the health of a pregnant individual and/or fetus, or when a fetus has a poor prognosis or life-limiting diagnosis. It is distinct from the American College of Obstetricians and Gynecologists identification of all abortions as medically indicated. Common indications for TFMR include life-threatening pregnancy complications (eg, placental abruption, hyperemesis gravidarum, exacerbation of psychiatric illness), chromosomal abnormalities (eg, Trisomy 13, 18, and 21; Klinefelter syndrome), and fetal anomalies (eg, neural tube defects, cardiac defects, renal agenesis). In this article, we discuss the negative psychological outcomes of TFMR, and how to screen and intervene to best help women who experience TFMR.

Psychiatric sequelae of TFMR

Unlike abortions in general, negative psychological outcomes are common among women who experience TFMR.¹ Nearly one-half of women develop symptoms of posttraumatic stress disorder (PTSD), and approximately one-fourth show signs of depression at 4 months after termination.² Such symptoms usually improve with time but may return around trauma anniversaries (date of diagnosis or termination). Women with a history of trauma, a prior psychiatric diagnosis, and/or no living children are at greater risk. Self-blame, doubt, and high levels of distress are also risk factors.^2-4 Protective factors include positive coping strategies (such as acceptance or reframing), higher perceived social support, and high self-efficacy.^3,4

Screening: What to ask, and how

Use open-ended questions to ask about a patient’s obstetric history:

• Have you ever been pregnant?
• If you’re comfortable sharing, what were the outcomes of these pregnancies?

If a woman discloses that she has experienced a TFMR, screen for and normalize psychiatric outcomes by asking:

• Symptoms of grief, depression, and anxiety are common after TFMR. Have you experienced such symptoms?
• What impact has terminating your pregnancy for medical reasons had on your mental health?

Screening tools such as the General Self-Efficacy Scale can help assess predictive factors, while other scales can assess specific diagnoses (eg, Patient Health Questionaire-9 for depression, Impact of Event Scale-Revised and PTSD Checklist for DSM-5 for trauma-related symptoms, Traumatic Grief Inventory Self Report Version for pathological grief). The Edinburgh Postnatal Depression Scale can assess for depression, but if you use this instrument, exclude statements that reference a current pregnancy or recent delivery.

How to best help

Interventions should be specific and targeted. Thus, consider the individual nature of the experience and variation in attachment that can occur over time.⁵ OB-GYN and perinatal psychiatry clinicians can recommend local resources and support groups that specifically focus on TFMR, rather than on general pregnancy loss. Refer patients to therapists who specialize in pregnancy loss, reproductive trauma, and/or TFMR. Cognitive-behavioral therapy and acceptance and commitment therapy may be appropriate and effective.³ Online support groups (such as Termination of Pregnancy for Medical Reasons; www.facebook.com/groups/TFMRgroup/) can supplement or fill gaps in local resources. Suggest books that discuss TFMR, such as Our Heartbreaking Choices: Forty-Six Women Share Their Stories of Interrupting a Much-Wanted Pregnancy.⁶ Also suggest ways to facilitate conversations with children around TFMR, which is described in a series of books by Katrina Villegas (https://shop.terminationsremembered.com/product-category/childrens-books-about-termination-for-medical-reasons/). Inquire about support rituals, such as naming their child, holding a memorial service, and/or recognizing their due date. Also, for a woman who has experienced TFMR, remember to screen for anxiety in subsequent pregnancies.

Termination of pregnancy for medical reasons (TFMR) occurs when a pregnancy is ended due to medical complications that threaten the health of a pregnant individual and/or fetus, or when a fetus has a poor prognosis or life-limiting diagnosis. It is distinct from the American College of Obstetricians and Gynecologists identification of all abortions as medically indicated. Common indications for TFMR include life-threatening pregnancy complications (eg, placental abruption, hyperemesis gravidarum, exacerbation of psychiatric illness), chromosomal abnormalities (eg, Trisomy 13, 18, and 21; Klinefelter syndrome), and fetal anomalies (eg, neural tube defects, cardiac defects, renal agenesis). In this article, we discuss the negative psychological outcomes of TFMR, and how to screen and intervene to best help women who experience TFMR.

Psychiatric sequelae of TFMR

Unlike abortions in general, negative psychological outcomes are common among women who experience TFMR.¹ Nearly one-half of women develop symptoms of posttraumatic stress disorder (PTSD), and approximately one-fourth show signs of depression at 4 months after termination.² Such symptoms usually improve with time but may return around trauma anniversaries (date of diagnosis or termination). Women with a history of trauma, a prior psychiatric diagnosis, and/or no living children are at greater risk. Self-blame, doubt, and high levels of distress are also risk factors.^2-4 Protective factors include positive coping strategies (such as acceptance or reframing), higher perceived social support, and high self-efficacy.^3,4

Screening: What to ask, and how

Use open-ended questions to ask about a patient’s obstetric history:

• Have you ever been pregnant?
• If you’re comfortable sharing, what were the outcomes of these pregnancies?

If a woman discloses that she has experienced a TFMR, screen for and normalize psychiatric outcomes by asking:

• Symptoms of grief, depression, and anxiety are common after TFMR. Have you experienced such symptoms?
• What impact has terminating your pregnancy for medical reasons had on your mental health?

Screening tools such as the General Self-Efficacy Scale can help assess predictive factors, while other scales can assess specific diagnoses (eg, Patient Health Questionaire-9 for depression, Impact of Event Scale-Revised and PTSD Checklist for DSM-5 for trauma-related symptoms, Traumatic Grief Inventory Self Report Version for pathological grief). The Edinburgh Postnatal Depression Scale can assess for depression, but if you use this instrument, exclude statements that reference a current pregnancy or recent delivery.

How to best help

Interventions should be specific and targeted. Thus, consider the individual nature of the experience and variation in attachment that can occur over time.⁵ OB-GYN and perinatal psychiatry clinicians can recommend local resources and support groups that specifically focus on TFMR, rather than on general pregnancy loss. Refer patients to therapists who specialize in pregnancy loss, reproductive trauma, and/or TFMR. Cognitive-behavioral therapy and acceptance and commitment therapy may be appropriate and effective.³ Online support groups (such as Termination of Pregnancy for Medical Reasons; www.facebook.com/groups/TFMRgroup/) can supplement or fill gaps in local resources. Suggest books that discuss TFMR, such as Our Heartbreaking Choices: Forty-Six Women Share Their Stories of Interrupting a Much-Wanted Pregnancy.⁶ Also suggest ways to facilitate conversations with children around TFMR, which is described in a series of books by Katrina Villegas (https://shop.terminationsremembered.com/product-category/childrens-books-about-termination-for-medical-reasons/). Inquire about support rituals, such as naming their child, holding a memorial service, and/or recognizing their due date. Also, for a woman who has experienced TFMR, remember to screen for anxiety in subsequent pregnancies.

Termination of pregnancy for medical reasons (TFMR) occurs when a pregnancy is ended due to medical complications that threaten the health of a pregnant individual and/or fetus, or when a fetus has a poor prognosis or life-limiting diagnosis. It is distinct from the American College of Obstetricians and Gynecologists identification of all abortions as medically indicated. Common indications for TFMR include life-threatening pregnancy complications (eg, placental abruption, hyperemesis gravidarum, exacerbation of psychiatric illness), chromosomal abnormalities (eg, Trisomy 13, 18, and 21; Klinefelter syndrome), and fetal anomalies (eg, neural tube defects, cardiac defects, renal agenesis). In this article, we discuss the negative psychological outcomes of TFMR, and how to screen and intervene to best help women who experience TFMR.

Psychiatric sequelae of TFMR

Unlike abortions in general, negative psychological outcomes are common among women who experience TFMR.¹ Nearly one-half of women develop symptoms of posttraumatic stress disorder (PTSD), and approximately one-fourth show signs of depression at 4 months after termination.² Such symptoms usually improve with time but may return around trauma anniversaries (date of diagnosis or termination). Women with a history of trauma, a prior psychiatric diagnosis, and/or no living children are at greater risk. Self-blame, doubt, and high levels of distress are also risk factors.^2-4 Protective factors include positive coping strategies (such as acceptance or reframing), higher perceived social support, and high self-efficacy.^3,4

Screening: What to ask, and how

Use open-ended questions to ask about a patient’s obstetric history:

• Have you ever been pregnant?
• If you’re comfortable sharing, what were the outcomes of these pregnancies?

If a woman discloses that she has experienced a TFMR, screen for and normalize psychiatric outcomes by asking:

• Symptoms of grief, depression, and anxiety are common after TFMR. Have you experienced such symptoms?
• What impact has terminating your pregnancy for medical reasons had on your mental health?

Screening tools such as the General Self-Efficacy Scale can help assess predictive factors, while other scales can assess specific diagnoses (eg, Patient Health Questionaire-9 for depression, Impact of Event Scale-Revised and PTSD Checklist for DSM-5 for trauma-related symptoms, Traumatic Grief Inventory Self Report Version for pathological grief). The Edinburgh Postnatal Depression Scale can assess for depression, but if you use this instrument, exclude statements that reference a current pregnancy or recent delivery.

How to best help

Interventions should be specific and targeted. Thus, consider the individual nature of the experience and variation in attachment that can occur over time.⁵ OB-GYN and perinatal psychiatry clinicians can recommend local resources and support groups that specifically focus on TFMR, rather than on general pregnancy loss. Refer patients to therapists who specialize in pregnancy loss, reproductive trauma, and/or TFMR. Cognitive-behavioral therapy and acceptance and commitment therapy may be appropriate and effective.³ Online support groups (such as Termination of Pregnancy for Medical Reasons; www.facebook.com/groups/TFMRgroup/) can supplement or fill gaps in local resources. Suggest books that discuss TFMR, such as Our Heartbreaking Choices: Forty-Six Women Share Their Stories of Interrupting a Much-Wanted Pregnancy.⁶ Also suggest ways to facilitate conversations with children around TFMR, which is described in a series of books by Katrina Villegas (https://shop.terminationsremembered.com/product-category/childrens-books-about-termination-for-medical-reasons/). Inquire about support rituals, such as naming their child, holding a memorial service, and/or recognizing their due date. Also, for a woman who has experienced TFMR, remember to screen for anxiety in subsequent pregnancies.

In patients with attention-deficit/hyperactivity disorder (ADHD), stimulants reduce impulsivity and improve attention and focus. In individuals who do not have this disorder, stimulants are believed to enhance cognition, attention, and physical performance. In this article, I describe how a patient whose intermittent use of stimulants for motivation and cognitive enhancement shaped my approach to the diagnosis of ADHD.

Instant gratification and quick solutions

When I joined my psychiatry residency program, I expected to primarily treat patients who had depression, bipolar disorder, or psychosis. However, as I transitioned to my second year of residency, most patients I was assigned to had been diagnosed with ADHD. One of them was a 30-year-old in his fourth year of dental school. On his first visit, he requested a refill of dextroamphetamine and amphetamine 10 mg twice a day. He had been diagnosed with ADHD 5 years ago. He explained that he only needed this medication when preparing for his board examinations to motivate him and boost his focus and retention before studying. His study schedule included the exact doses and times he planned to take his stimulant.

I asked him questions to confirm the diagnosis, but he rushed to reassure me that he had already been diagnosed with ADHD and had been doing well on dextroamphetamine and amphetamine for many years. I was inclined to question his diagnosis of ADHD after learning of his “as-needed” use of stimulants as brain enhancers. His medical record reflecting the diagnosis of ADHD dated back to when he was a first-year dental student. The diagnosis was based on the patient’s report of procrastination for as long as he could remember. It also hinged on difficulties learning a second language and math being a challenging subject for him. Despite this, he managed to do well in school and earn an undergraduate degree, well enough to later pursue dentistry at a reputable university.

I thought, “Isn’t it normal to lose motivation and have doubts when preparing for a high-stakes exam like the boards? Aren’t these negative thoughts distracting enough to render sustained focus impossible? Doesn’t everyone struggle with procrastination, especially when they need to study? If learning a new language requires devotion, consistency, and sacrifice, isn’t it inherently challenging? Doesn’t good performance in math depend on multiple factors (ie, a strong foundation, cumulative learning, frequent practice), and thus leaves many students struggling?”

This interaction and many similar ones made me scrutinize the diagnosis of ADHD in patients I encounter in clinical settings. We live in a society where instant gratification is cherished, and quick fixes are pursued with little contemplation of pitfalls. Students use stimulants to cram for exams, high-functioning professionals use them to meet deadlines, and athletes use them to enhance performance and improve reaction times. Psychiatry seems to be drawn into the demands of society and may be fueling the “quick-fix” mentality by prescribing stimulants to healthy individuals who want to improve their focus, and then diagnosing them with ADHD to align the prescription with an appropriate diagnosis. Research on the adverse effects of stimulant use in adults is not convincing nor conclusive enough to sway prescribers from denying the average adult patient a stimulant to enhance cognitive function before a high-stakes exam or a critical, career-shaping project if they present with some ADHD traits, which the patient might even hyperbolize to secure the desired prescription. All of this may contribute to the perceived rising prevalence of ADHD among adults.

As for my 30-year-old dental student, I reasoned that continuing his medication, for now, would help me establish rapport and trust. This would allow me to counsel him on the long-term adverse effects of stimulants, and develop a plan to optimize his sleep, focus, and time management skills, eventually improving his cognition and attention naturally. Unfortunately, he did not show up to future appointments after I sent him the refill.

In patients with attention-deficit/hyperactivity disorder (ADHD), stimulants reduce impulsivity and improve attention and focus. In individuals who do not have this disorder, stimulants are believed to enhance cognition, attention, and physical performance. In this article, I describe how a patient whose intermittent use of stimulants for motivation and cognitive enhancement shaped my approach to the diagnosis of ADHD.

Instant gratification and quick solutions

When I joined my psychiatry residency program, I expected to primarily treat patients who had depression, bipolar disorder, or psychosis. However, as I transitioned to my second year of residency, most patients I was assigned to had been diagnosed with ADHD. One of them was a 30-year-old in his fourth year of dental school. On his first visit, he requested a refill of dextroamphetamine and amphetamine 10 mg twice a day. He had been diagnosed with ADHD 5 years ago. He explained that he only needed this medication when preparing for his board examinations to motivate him and boost his focus and retention before studying. His study schedule included the exact doses and times he planned to take his stimulant.

I asked him questions to confirm the diagnosis, but he rushed to reassure me that he had already been diagnosed with ADHD and had been doing well on dextroamphetamine and amphetamine for many years. I was inclined to question his diagnosis of ADHD after learning of his “as-needed” use of stimulants as brain enhancers. His medical record reflecting the diagnosis of ADHD dated back to when he was a first-year dental student. The diagnosis was based on the patient’s report of procrastination for as long as he could remember. It also hinged on difficulties learning a second language and math being a challenging subject for him. Despite this, he managed to do well in school and earn an undergraduate degree, well enough to later pursue dentistry at a reputable university.

I thought, “Isn’t it normal to lose motivation and have doubts when preparing for a high-stakes exam like the boards? Aren’t these negative thoughts distracting enough to render sustained focus impossible? Doesn’t everyone struggle with procrastination, especially when they need to study? If learning a new language requires devotion, consistency, and sacrifice, isn’t it inherently challenging? Doesn’t good performance in math depend on multiple factors (ie, a strong foundation, cumulative learning, frequent practice), and thus leaves many students struggling?”

This interaction and many similar ones made me scrutinize the diagnosis of ADHD in patients I encounter in clinical settings. We live in a society where instant gratification is cherished, and quick fixes are pursued with little contemplation of pitfalls. Students use stimulants to cram for exams, high-functioning professionals use them to meet deadlines, and athletes use them to enhance performance and improve reaction times. Psychiatry seems to be drawn into the demands of society and may be fueling the “quick-fix” mentality by prescribing stimulants to healthy individuals who want to improve their focus, and then diagnosing them with ADHD to align the prescription with an appropriate diagnosis. Research on the adverse effects of stimulant use in adults is not convincing nor conclusive enough to sway prescribers from denying the average adult patient a stimulant to enhance cognitive function before a high-stakes exam or a critical, career-shaping project if they present with some ADHD traits, which the patient might even hyperbolize to secure the desired prescription. All of this may contribute to the perceived rising prevalence of ADHD among adults.

As for my 30-year-old dental student, I reasoned that continuing his medication, for now, would help me establish rapport and trust. This would allow me to counsel him on the long-term adverse effects of stimulants, and develop a plan to optimize his sleep, focus, and time management skills, eventually improving his cognition and attention naturally. Unfortunately, he did not show up to future appointments after I sent him the refill.

In patients with attention-deficit/hyperactivity disorder (ADHD), stimulants reduce impulsivity and improve attention and focus. In individuals who do not have this disorder, stimulants are believed to enhance cognition, attention, and physical performance. In this article, I describe how a patient whose intermittent use of stimulants for motivation and cognitive enhancement shaped my approach to the diagnosis of ADHD.

Instant gratification and quick solutions

When I joined my psychiatry residency program, I expected to primarily treat patients who had depression, bipolar disorder, or psychosis. However, as I transitioned to my second year of residency, most patients I was assigned to had been diagnosed with ADHD. One of them was a 30-year-old in his fourth year of dental school. On his first visit, he requested a refill of dextroamphetamine and amphetamine 10 mg twice a day. He had been diagnosed with ADHD 5 years ago. He explained that he only needed this medication when preparing for his board examinations to motivate him and boost his focus and retention before studying. His study schedule included the exact doses and times he planned to take his stimulant.

I asked him questions to confirm the diagnosis, but he rushed to reassure me that he had already been diagnosed with ADHD and had been doing well on dextroamphetamine and amphetamine for many years. I was inclined to question his diagnosis of ADHD after learning of his “as-needed” use of stimulants as brain enhancers. His medical record reflecting the diagnosis of ADHD dated back to when he was a first-year dental student. The diagnosis was based on the patient’s report of procrastination for as long as he could remember. It also hinged on difficulties learning a second language and math being a challenging subject for him. Despite this, he managed to do well in school and earn an undergraduate degree, well enough to later pursue dentistry at a reputable university.

I thought, “Isn’t it normal to lose motivation and have doubts when preparing for a high-stakes exam like the boards? Aren’t these negative thoughts distracting enough to render sustained focus impossible? Doesn’t everyone struggle with procrastination, especially when they need to study? If learning a new language requires devotion, consistency, and sacrifice, isn’t it inherently challenging? Doesn’t good performance in math depend on multiple factors (ie, a strong foundation, cumulative learning, frequent practice), and thus leaves many students struggling?”

This interaction and many similar ones made me scrutinize the diagnosis of ADHD in patients I encounter in clinical settings. We live in a society where instant gratification is cherished, and quick fixes are pursued with little contemplation of pitfalls. Students use stimulants to cram for exams, high-functioning professionals use them to meet deadlines, and athletes use them to enhance performance and improve reaction times. Psychiatry seems to be drawn into the demands of society and may be fueling the “quick-fix” mentality by prescribing stimulants to healthy individuals who want to improve their focus, and then diagnosing them with ADHD to align the prescription with an appropriate diagnosis. Research on the adverse effects of stimulant use in adults is not convincing nor conclusive enough to sway prescribers from denying the average adult patient a stimulant to enhance cognitive function before a high-stakes exam or a critical, career-shaping project if they present with some ADHD traits, which the patient might even hyperbolize to secure the desired prescription. All of this may contribute to the perceived rising prevalence of ADHD among adults.

As for my 30-year-old dental student, I reasoned that continuing his medication, for now, would help me establish rapport and trust. This would allow me to counsel him on the long-term adverse effects of stimulants, and develop a plan to optimize his sleep, focus, and time management skills, eventually improving his cognition and attention naturally. Unfortunately, he did not show up to future appointments after I sent him the refill.

Fifteen years is a lifetime for the advancement of medical research. This seems particularly true for upper GI tract disorders.

In 2007, eosinophilic esophagitis was a rare disease; limited clinical data were available describing the symptoms, demographic characteristics, and endoscopic findings. Treatment was guided mostly by uncontrolled patient series for topical steroids and comprehensive diet exclusion therapy. Today, the molecular, genetic, and evolving microbiome’s contributions to EoE are being elucidated. EoE is recognized as one of the most common diseases in our practice, and rigorously performed controlled trials of steroids and biologics (including Food and Drug Administration–approved dupilumab) guide our treatment. Diet has also become easier with the identification of a single food antigen as the cause in 40% of EoE patients. The most pressing need is for a test that’s reliable and less invasive than endoscopy to assess and monitor treatment.

Dr. Katzka is professor of medicine at Columbia University, New York. He reports consulting for Takeda and Celgene.

This article was updated July 7, 2022.

Fifteen years is a lifetime for the advancement of medical research. This seems particularly true for upper GI tract disorders.

In 2007, eosinophilic esophagitis was a rare disease; limited clinical data were available describing the symptoms, demographic characteristics, and endoscopic findings. Treatment was guided mostly by uncontrolled patient series for topical steroids and comprehensive diet exclusion therapy. Today, the molecular, genetic, and evolving microbiome’s contributions to EoE are being elucidated. EoE is recognized as one of the most common diseases in our practice, and rigorously performed controlled trials of steroids and biologics (including Food and Drug Administration–approved dupilumab) guide our treatment. Diet has also become easier with the identification of a single food antigen as the cause in 40% of EoE patients. The most pressing need is for a test that’s reliable and less invasive than endoscopy to assess and monitor treatment.

Dr. Katzka is professor of medicine at Columbia University, New York. He reports consulting for Takeda and Celgene.

This article was updated July 7, 2022.

Fifteen years is a lifetime for the advancement of medical research. This seems particularly true for upper GI tract disorders.

In 2007, eosinophilic esophagitis was a rare disease; limited clinical data were available describing the symptoms, demographic characteristics, and endoscopic findings. Treatment was guided mostly by uncontrolled patient series for topical steroids and comprehensive diet exclusion therapy. Today, the molecular, genetic, and evolving microbiome’s contributions to EoE are being elucidated. EoE is recognized as one of the most common diseases in our practice, and rigorously performed controlled trials of steroids and biologics (including Food and Drug Administration–approved dupilumab) guide our treatment. Diet has also become easier with the identification of a single food antigen as the cause in 40% of EoE patients. The most pressing need is for a test that’s reliable and less invasive than endoscopy to assess and monitor treatment.

Dr. Katzka is professor of medicine at Columbia University, New York. He reports consulting for Takeda and Celgene.

This article was updated July 7, 2022.

What characteristics or symptoms do you look for to identify patients who are at risk for exocrine pancreatic insufficiency (EPI)?

Dr. Barkin: The first thing we have to understand is which patient populations we should consider. EPI traditionally has been a disease associated with chronic pancreatitis, and that still makes up the majority of patients. But in addition to those with chronic pancreatitis, we have to think about patients who have had severe acute pancreatitis and who may have had loss of functional pancreatic parenchyma or pancreatic surgery, as well as patients with pancreatic cancer that may cause both ductal obstruction and parenchyma loss.

This might also include patients with foregut surgery who may develop postcibal dyskinesia, meaning they do not get appropriate mixing of the gastric chyme and food contents with the pancreatic enzymes and pancreatic juice in the duodenum. For example, this might be evident in patients who have had a Roux-en-Y gastric bypass, or in patients with untreated celiac disease, who do not get stimulation for pancreatic secretion based on the amount of small bowel mucosal damage.

A series of other conditions may present with EPI, such as inflammatory bowel disease, although these make up the minority of cases. When we think about symptoms, the end symptom of EPI from fat malabsorption is gross steatorrhea. Unfortunately, by the time the patient gets to that point, the cat is out of the bag—especially in patients with chronic pancreatitis. So, we want to try to identify these patients earlier.

Realistically, a series of symptoms can be seen far earlier than gross steatorrhea. In fact, most patients will present with symptoms like increased stool frequency or decreased stool consistency in their daily life. Some abdominal discomfort or bloating may be seen that is associated with maldigestion of  food, among other factors.

In some patients, night vision changes from fat-soluble vitamin deficiencies may be the first or an early presenting symptom if they have other conditions masking their diarrheal symptoms. Patients who do not feel well when they are eating or feel uncomfortable after they eat may avoid certain types of foods. You may see weight loss in these populations because they are avoiding foods, feeling sitophobia, or not appropriately digesting their food.

Unfortunately, even before we see clinically relevant symptoms, we may see micronutrient deficiencies and fat-soluble vitamin deficiencies. That is why it is so important, for example, in the chronic pancreatitis population, to screen these patients on a regular basis for the presence of EPI, whether with symptom questionnaires or by testing.

Can you expand on some of the risk factors and the importance of screening, particularly for malnutrition?

Dr. Barkin: The risk factors usually involve patients who have had some kind of damage to the gland. For example, many patients with cystic fibrosis are actually exocrine pancreatic insufficient from early in life to diagnosis. They have loss of the gland and loss of function at the gland.

Our patients with chronic pancreatitis, who may have had either recurrent acute pancreatitis or chronic pancreatitis for a variety of reasons, are screened for EPI on a regular basis. That may mean that you ask them a symptom questionnaire at each clinic visit and check a fecal elastase level on a regular basis. It is not just the symptoms that we have to worry about; we have to think about the effects of maldigestion on a patient’s weight and nutritional status and the impact of micronutrient deficiencies.

A series of new studies has looked at the impact of exocrine insufficiency. For example, a study from Spain found an increased risk of all-cause mortality with exocrine insufficiency. When we think about metabolic bone disease in this population with exocrine insufficiency, we see that there is decreased bone density and increased risk of pathologic low-trauma fractures. For example, the patient who has fallen from a standing position at home and suddenly has a hip fracture has substantial morbidity and mortality associated with that fracture. The decreases in bone density and increased risk of fracture are reversed when we identify EPI and treat it appropriately.

What is your approach to diagnosing EPI?

Dr. Barkin: For a patient who walks in the door with an obvious diagnosis or prior diagnosis of chronic pancreatitis, it is relatively easy to ask them a series of questions about whether they have symptoms that may be associated with EPI. So, first, I ask them about their bowel habits and stool frequency and consistency.

A couple of years ago, we showed that if you treat a patient with EPI using pancreatic enzyme replacement therapy, their stool consistency and frequency are the two reliable markers that get better. They not only get better, but these improvements directly correlate with objective stool markers of improvement in fat maldigestion.

Obviously, we want improvement in other symptoms—abdominal discomfort, bloating, etc.—but I have to set very realistic expectations for patients. Along with stool frequency and consistency, there should be subsequent improvement of steatorrhea. I talk to them about the importance of taking a multivitamin to prevent those micronutrient deficiencies. We check for micronutrient deficiencies and fat-soluble vitamin deficiencies routinely.

Patients who do not have obvious chronic pancreatitis who get diagnosed with EPI are a little bit harder to parse out. I want to make sure that they do not have celiac disease, or that they do not have a concomitant mimicking symptom that may result in, for example, a low fecal elastase level. I also check for small intestinal bacterial overgrowth (SIBO) as a mimicking condition.

Regarding fecal elastase testing, the gold standard for diagnosis of EPI was historically a 72-hour fecal fat collection on a standardized-fat-intake diet. That required patient confinement in the hospital. It is cumbersome, not widely available, and not realistic in practice.

In some centers, endoscopic pancreatic function testing, secretin-enhanced magnetic resonance cholangiopancreatography (MRCP), or breath testing, as is done in Europe, may be options to help diagnose EPI, but these tests are not widely available. Unfortunately, we do not have a great diagnostic test for exocrine insufficiency. As a result, we use fecal elastase level. If you have a patient who has a high pretest probability of having EPI, it is a relatively good test. If they have a low pretest probability, then a series of false-positive test results may occur in this patient population. That means they may not actually have exocrine insufficiency.

If a diarrheal stool is submitted for testing, a false-positive fecal elastase test may result. That is really key, because I see a number of patients with potentially functional diarrheal symptoms who also have low fecal elastase levels. As a result, they have been labeled as exocrine insufficient when, in fact, they may not actually have the disease, which is why it is so important to understand and think about that.

How do you choose the appropriate approach to managing EPI, and how do you consider the impact it has on the quality of life overall?

Dr. Barkin: There are two key points. The treatment for EPI is not to tell your patient to not eat fat and hope that it gets better. Rather, it is appropriate supplementation of pancreatic enzymes. This is done with pancreatic enzyme replacement therapy. A few FDA-approved medications are on the market. I recommend against the ones that have been labeled as pancreatic enzyme digestive aids that are available online. Those are not pancreatic enzymes; a regulatory push about 15 to 20 years ago got these digestive aids appropriately regulated.

The FDA-approved medications are dosed at approximately 40,000 to 50,000 lipase units per meal to start, according to the guidelines. Some of us may prescribe higher doses than that to start. These are taken with meals and about a half-dose with snacks.

If you have a patient who is taking, for example, two pills per meal or two capsules per meal, it is important that they take one at the very beginning of the meal and one about halfway through the meal. The pills should not be taken a half hour before or a half hour after the meal. The goal is to simulate normal pancreatic function as much as possible to get the food contents mixing.

The pancreatic enzymes come in a coated version that does not require coadministration with proton pump inhibitors or an uncoated version that does require coadministration of proton pump inhibitors to prevent degradation by gastric acid. Patients need to understand that, although they may take a large number of pills per day, adhering to this regimen is important, not only for treating their symptoms, but also for combating long-term morbidity and mortality.

I use the symptomatic response to assess response to therapy because, as discussed, there is a direct correlation between improvements in stool frequency and consistency and objective markers of response to therapy.

If a patient is not responding, we first check to make sure that there are no adherence issues and that they are able to access therapy, because sometimes there are issues with cost or insurance approvals. Second, I make sure that patients are taking it correctly, and that they understand the difference between a meal and a snack. For example, if somebody says, “Oh, I just had a small cheeseburger and that's my snack,” that is actually a meal and may require more enzymes. Once we ensure that those are not issues, I make sure again, as part of my approach, that there are no comorbid conditions that may be driving some of the symptoms, such as celiac disease or SIBO, with SIBO being very common in this population.

Then we have to decide whether we need to change the dose. Do we need to increase the dose? Some of us start a little bit higher than the 40,000 to 50,000 units of lipase per meal, as suggested in some of our national and international guidelines, and go from there.

What characteristics or symptoms do you look for to identify patients who are at risk for exocrine pancreatic insufficiency (EPI)?

Dr. Barkin: The first thing we have to understand is which patient populations we should consider. EPI traditionally has been a disease associated with chronic pancreatitis, and that still makes up the majority of patients. But in addition to those with chronic pancreatitis, we have to think about patients who have had severe acute pancreatitis and who may have had loss of functional pancreatic parenchyma or pancreatic surgery, as well as patients with pancreatic cancer that may cause both ductal obstruction and parenchyma loss.

This might also include patients with foregut surgery who may develop postcibal dyskinesia, meaning they do not get appropriate mixing of the gastric chyme and food contents with the pancreatic enzymes and pancreatic juice in the duodenum. For example, this might be evident in patients who have had a Roux-en-Y gastric bypass, or in patients with untreated celiac disease, who do not get stimulation for pancreatic secretion based on the amount of small bowel mucosal damage.

A series of other conditions may present with EPI, such as inflammatory bowel disease, although these make up the minority of cases. When we think about symptoms, the end symptom of EPI from fat malabsorption is gross steatorrhea. Unfortunately, by the time the patient gets to that point, the cat is out of the bag—especially in patients with chronic pancreatitis. So, we want to try to identify these patients earlier.

Realistically, a series of symptoms can be seen far earlier than gross steatorrhea. In fact, most patients will present with symptoms like increased stool frequency or decreased stool consistency in their daily life. Some abdominal discomfort or bloating may be seen that is associated with maldigestion of  food, among other factors.

In some patients, night vision changes from fat-soluble vitamin deficiencies may be the first or an early presenting symptom if they have other conditions masking their diarrheal symptoms. Patients who do not feel well when they are eating or feel uncomfortable after they eat may avoid certain types of foods. You may see weight loss in these populations because they are avoiding foods, feeling sitophobia, or not appropriately digesting their food.

Unfortunately, even before we see clinically relevant symptoms, we may see micronutrient deficiencies and fat-soluble vitamin deficiencies. That is why it is so important, for example, in the chronic pancreatitis population, to screen these patients on a regular basis for the presence of EPI, whether with symptom questionnaires or by testing.

Can you expand on some of the risk factors and the importance of screening, particularly for malnutrition?

Dr. Barkin: The risk factors usually involve patients who have had some kind of damage to the gland. For example, many patients with cystic fibrosis are actually exocrine pancreatic insufficient from early in life to diagnosis. They have loss of the gland and loss of function at the gland.

Our patients with chronic pancreatitis, who may have had either recurrent acute pancreatitis or chronic pancreatitis for a variety of reasons, are screened for EPI on a regular basis. That may mean that you ask them a symptom questionnaire at each clinic visit and check a fecal elastase level on a regular basis. It is not just the symptoms that we have to worry about; we have to think about the effects of maldigestion on a patient’s weight and nutritional status and the impact of micronutrient deficiencies.

A series of new studies has looked at the impact of exocrine insufficiency. For example, a study from Spain found an increased risk of all-cause mortality with exocrine insufficiency. When we think about metabolic bone disease in this population with exocrine insufficiency, we see that there is decreased bone density and increased risk of pathologic low-trauma fractures. For example, the patient who has fallen from a standing position at home and suddenly has a hip fracture has substantial morbidity and mortality associated with that fracture. The decreases in bone density and increased risk of fracture are reversed when we identify EPI and treat it appropriately.

What is your approach to diagnosing EPI?

Dr. Barkin: For a patient who walks in the door with an obvious diagnosis or prior diagnosis of chronic pancreatitis, it is relatively easy to ask them a series of questions about whether they have symptoms that may be associated with EPI. So, first, I ask them about their bowel habits and stool frequency and consistency.

A couple of years ago, we showed that if you treat a patient with EPI using pancreatic enzyme replacement therapy, their stool consistency and frequency are the two reliable markers that get better. They not only get better, but these improvements directly correlate with objective stool markers of improvement in fat maldigestion.

Obviously, we want improvement in other symptoms—abdominal discomfort, bloating, etc.—but I have to set very realistic expectations for patients. Along with stool frequency and consistency, there should be subsequent improvement of steatorrhea. I talk to them about the importance of taking a multivitamin to prevent those micronutrient deficiencies. We check for micronutrient deficiencies and fat-soluble vitamin deficiencies routinely.

Patients who do not have obvious chronic pancreatitis who get diagnosed with EPI are a little bit harder to parse out. I want to make sure that they do not have celiac disease, or that they do not have a concomitant mimicking symptom that may result in, for example, a low fecal elastase level. I also check for small intestinal bacterial overgrowth (SIBO) as a mimicking condition.

Regarding fecal elastase testing, the gold standard for diagnosis of EPI was historically a 72-hour fecal fat collection on a standardized-fat-intake diet. That required patient confinement in the hospital. It is cumbersome, not widely available, and not realistic in practice.

In some centers, endoscopic pancreatic function testing, secretin-enhanced magnetic resonance cholangiopancreatography (MRCP), or breath testing, as is done in Europe, may be options to help diagnose EPI, but these tests are not widely available. Unfortunately, we do not have a great diagnostic test for exocrine insufficiency. As a result, we use fecal elastase level. If you have a patient who has a high pretest probability of having EPI, it is a relatively good test. If they have a low pretest probability, then a series of false-positive test results may occur in this patient population. That means they may not actually have exocrine insufficiency.

If a diarrheal stool is submitted for testing, a false-positive fecal elastase test may result. That is really key, because I see a number of patients with potentially functional diarrheal symptoms who also have low fecal elastase levels. As a result, they have been labeled as exocrine insufficient when, in fact, they may not actually have the disease, which is why it is so important to understand and think about that.

How do you choose the appropriate approach to managing EPI, and how do you consider the impact it has on the quality of life overall?

Dr. Barkin: There are two key points. The treatment for EPI is not to tell your patient to not eat fat and hope that it gets better. Rather, it is appropriate supplementation of pancreatic enzymes. This is done with pancreatic enzyme replacement therapy. A few FDA-approved medications are on the market. I recommend against the ones that have been labeled as pancreatic enzyme digestive aids that are available online. Those are not pancreatic enzymes; a regulatory push about 15 to 20 years ago got these digestive aids appropriately regulated.

The FDA-approved medications are dosed at approximately 40,000 to 50,000 lipase units per meal to start, according to the guidelines. Some of us may prescribe higher doses than that to start. These are taken with meals and about a half-dose with snacks.

If you have a patient who is taking, for example, two pills per meal or two capsules per meal, it is important that they take one at the very beginning of the meal and one about halfway through the meal. The pills should not be taken a half hour before or a half hour after the meal. The goal is to simulate normal pancreatic function as much as possible to get the food contents mixing.

The pancreatic enzymes come in a coated version that does not require coadministration with proton pump inhibitors or an uncoated version that does require coadministration of proton pump inhibitors to prevent degradation by gastric acid. Patients need to understand that, although they may take a large number of pills per day, adhering to this regimen is important, not only for treating their symptoms, but also for combating long-term morbidity and mortality.

I use the symptomatic response to assess response to therapy because, as discussed, there is a direct correlation between improvements in stool frequency and consistency and objective markers of response to therapy.

If a patient is not responding, we first check to make sure that there are no adherence issues and that they are able to access therapy, because sometimes there are issues with cost or insurance approvals. Second, I make sure that patients are taking it correctly, and that they understand the difference between a meal and a snack. For example, if somebody says, “Oh, I just had a small cheeseburger and that's my snack,” that is actually a meal and may require more enzymes. Once we ensure that those are not issues, I make sure again, as part of my approach, that there are no comorbid conditions that may be driving some of the symptoms, such as celiac disease or SIBO, with SIBO being very common in this population.

Then we have to decide whether we need to change the dose. Do we need to increase the dose? Some of us start a little bit higher than the 40,000 to 50,000 units of lipase per meal, as suggested in some of our national and international guidelines, and go from there.

What characteristics or symptoms do you look for to identify patients who are at risk for exocrine pancreatic insufficiency (EPI)?

Dr. Barkin: The first thing we have to understand is which patient populations we should consider. EPI traditionally has been a disease associated with chronic pancreatitis, and that still makes up the majority of patients. But in addition to those with chronic pancreatitis, we have to think about patients who have had severe acute pancreatitis and who may have had loss of functional pancreatic parenchyma or pancreatic surgery, as well as patients with pancreatic cancer that may cause both ductal obstruction and parenchyma loss.

This might also include patients with foregut surgery who may develop postcibal dyskinesia, meaning they do not get appropriate mixing of the gastric chyme and food contents with the pancreatic enzymes and pancreatic juice in the duodenum. For example, this might be evident in patients who have had a Roux-en-Y gastric bypass, or in patients with untreated celiac disease, who do not get stimulation for pancreatic secretion based on the amount of small bowel mucosal damage.

A series of other conditions may present with EPI, such as inflammatory bowel disease, although these make up the minority of cases. When we think about symptoms, the end symptom of EPI from fat malabsorption is gross steatorrhea. Unfortunately, by the time the patient gets to that point, the cat is out of the bag—especially in patients with chronic pancreatitis. So, we want to try to identify these patients earlier.

Realistically, a series of symptoms can be seen far earlier than gross steatorrhea. In fact, most patients will present with symptoms like increased stool frequency or decreased stool consistency in their daily life. Some abdominal discomfort or bloating may be seen that is associated with maldigestion of  food, among other factors.

In some patients, night vision changes from fat-soluble vitamin deficiencies may be the first or an early presenting symptom if they have other conditions masking their diarrheal symptoms. Patients who do not feel well when they are eating or feel uncomfortable after they eat may avoid certain types of foods. You may see weight loss in these populations because they are avoiding foods, feeling sitophobia, or not appropriately digesting their food.

Unfortunately, even before we see clinically relevant symptoms, we may see micronutrient deficiencies and fat-soluble vitamin deficiencies. That is why it is so important, for example, in the chronic pancreatitis population, to screen these patients on a regular basis for the presence of EPI, whether with symptom questionnaires or by testing.

Can you expand on some of the risk factors and the importance of screening, particularly for malnutrition?

Dr. Barkin: The risk factors usually involve patients who have had some kind of damage to the gland. For example, many patients with cystic fibrosis are actually exocrine pancreatic insufficient from early in life to diagnosis. They have loss of the gland and loss of function at the gland.

Our patients with chronic pancreatitis, who may have had either recurrent acute pancreatitis or chronic pancreatitis for a variety of reasons, are screened for EPI on a regular basis. That may mean that you ask them a symptom questionnaire at each clinic visit and check a fecal elastase level on a regular basis. It is not just the symptoms that we have to worry about; we have to think about the effects of maldigestion on a patient’s weight and nutritional status and the impact of micronutrient deficiencies.

A series of new studies has looked at the impact of exocrine insufficiency. For example, a study from Spain found an increased risk of all-cause mortality with exocrine insufficiency. When we think about metabolic bone disease in this population with exocrine insufficiency, we see that there is decreased bone density and increased risk of pathologic low-trauma fractures. For example, the patient who has fallen from a standing position at home and suddenly has a hip fracture has substantial morbidity and mortality associated with that fracture. The decreases in bone density and increased risk of fracture are reversed when we identify EPI and treat it appropriately.

What is your approach to diagnosing EPI?

Dr. Barkin: For a patient who walks in the door with an obvious diagnosis or prior diagnosis of chronic pancreatitis, it is relatively easy to ask them a series of questions about whether they have symptoms that may be associated with EPI. So, first, I ask them about their bowel habits and stool frequency and consistency.

A couple of years ago, we showed that if you treat a patient with EPI using pancreatic enzyme replacement therapy, their stool consistency and frequency are the two reliable markers that get better. They not only get better, but these improvements directly correlate with objective stool markers of improvement in fat maldigestion.

Obviously, we want improvement in other symptoms—abdominal discomfort, bloating, etc.—but I have to set very realistic expectations for patients. Along with stool frequency and consistency, there should be subsequent improvement of steatorrhea. I talk to them about the importance of taking a multivitamin to prevent those micronutrient deficiencies. We check for micronutrient deficiencies and fat-soluble vitamin deficiencies routinely.

Patients who do not have obvious chronic pancreatitis who get diagnosed with EPI are a little bit harder to parse out. I want to make sure that they do not have celiac disease, or that they do not have a concomitant mimicking symptom that may result in, for example, a low fecal elastase level. I also check for small intestinal bacterial overgrowth (SIBO) as a mimicking condition.

Regarding fecal elastase testing, the gold standard for diagnosis of EPI was historically a 72-hour fecal fat collection on a standardized-fat-intake diet. That required patient confinement in the hospital. It is cumbersome, not widely available, and not realistic in practice.

In some centers, endoscopic pancreatic function testing, secretin-enhanced magnetic resonance cholangiopancreatography (MRCP), or breath testing, as is done in Europe, may be options to help diagnose EPI, but these tests are not widely available. Unfortunately, we do not have a great diagnostic test for exocrine insufficiency. As a result, we use fecal elastase level. If you have a patient who has a high pretest probability of having EPI, it is a relatively good test. If they have a low pretest probability, then a series of false-positive test results may occur in this patient population. That means they may not actually have exocrine insufficiency.

If a diarrheal stool is submitted for testing, a false-positive fecal elastase test may result. That is really key, because I see a number of patients with potentially functional diarrheal symptoms who also have low fecal elastase levels. As a result, they have been labeled as exocrine insufficient when, in fact, they may not actually have the disease, which is why it is so important to understand and think about that.

How do you choose the appropriate approach to managing EPI, and how do you consider the impact it has on the quality of life overall?

Dr. Barkin: There are two key points. The treatment for EPI is not to tell your patient to not eat fat and hope that it gets better. Rather, it is appropriate supplementation of pancreatic enzymes. This is done with pancreatic enzyme replacement therapy. A few FDA-approved medications are on the market. I recommend against the ones that have been labeled as pancreatic enzyme digestive aids that are available online. Those are not pancreatic enzymes; a regulatory push about 15 to 20 years ago got these digestive aids appropriately regulated.

The FDA-approved medications are dosed at approximately 40,000 to 50,000 lipase units per meal to start, according to the guidelines. Some of us may prescribe higher doses than that to start. These are taken with meals and about a half-dose with snacks.

If you have a patient who is taking, for example, two pills per meal or two capsules per meal, it is important that they take one at the very beginning of the meal and one about halfway through the meal. The pills should not be taken a half hour before or a half hour after the meal. The goal is to simulate normal pancreatic function as much as possible to get the food contents mixing.

The pancreatic enzymes come in a coated version that does not require coadministration with proton pump inhibitors or an uncoated version that does require coadministration of proton pump inhibitors to prevent degradation by gastric acid. Patients need to understand that, although they may take a large number of pills per day, adhering to this regimen is important, not only for treating their symptoms, but also for combating long-term morbidity and mortality.

I use the symptomatic response to assess response to therapy because, as discussed, there is a direct correlation between improvements in stool frequency and consistency and objective markers of response to therapy.

If a patient is not responding, we first check to make sure that there are no adherence issues and that they are able to access therapy, because sometimes there are issues with cost or insurance approvals. Second, I make sure that patients are taking it correctly, and that they understand the difference between a meal and a snack. For example, if somebody says, “Oh, I just had a small cheeseburger and that's my snack,” that is actually a meal and may require more enzymes. Once we ensure that those are not issues, I make sure again, as part of my approach, that there are no comorbid conditions that may be driving some of the symptoms, such as celiac disease or SIBO, with SIBO being very common in this population.

Then we have to decide whether we need to change the dose. Do we need to increase the dose? Some of us start a little bit higher than the 40,000 to 50,000 units of lipase per meal, as suggested in some of our national and international guidelines, and go from there.

Patients with chronic obstructive pulmonary disease (COPD) typically have emphysema, which involves destruction of alveoli and reduction of elasticity leading to airflow obstruction, air trapping, and hyperinflation. Over time, these changes cause low respiratory reserve volume and increased residual volume, which cause dyspnea.  

One of the newest treatment options for patients who have advanced COPD with severe emphysema is a minimally invasive procedure called bronchoscopic lung volume reduction (BLVR). Most recently, the FDA approved the use of endobronchial valves for this procedure, which are implanted in the airways of the lungs to reduce air trapping and hyperinflation. 

In certain patients, BLVR has been shown to improve lung function, facilitate easier breathing, enhance exercise tolerance, and lead to better quality of life. 

In this ReCAP, Dr. Javier Diaz-Mendoza, program director of the Interventional Pulmonology Fellowship at Henry Ford Health System in Detroit, discusses the benefits of BLVR in patients who have advanced COPD with emphysema. He discusses the procedure, patient outcomes, and which patients should be considered for BLVR.  

--

Associate Professor of Medicine, Henry Ford Hospital, Wayne State University; Program Director, Interventional Pulmonology Fellowship, Henry Ford Health System, Detroit, MI

Javier Diaz-Mendoza, MD, FCCP, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Ion Intuitive Serve(d) as a speaker or a member of a speakers bureau for: Association of Interventional Pulmonology Program Directors

Patients with chronic obstructive pulmonary disease (COPD) typically have emphysema, which involves destruction of alveoli and reduction of elasticity leading to airflow obstruction, air trapping, and hyperinflation. Over time, these changes cause low respiratory reserve volume and increased residual volume, which cause dyspnea.  

One of the newest treatment options for patients who have advanced COPD with severe emphysema is a minimally invasive procedure called bronchoscopic lung volume reduction (BLVR). Most recently, the FDA approved the use of endobronchial valves for this procedure, which are implanted in the airways of the lungs to reduce air trapping and hyperinflation. 

In certain patients, BLVR has been shown to improve lung function, facilitate easier breathing, enhance exercise tolerance, and lead to better quality of life. 

In this ReCAP, Dr. Javier Diaz-Mendoza, program director of the Interventional Pulmonology Fellowship at Henry Ford Health System in Detroit, discusses the benefits of BLVR in patients who have advanced COPD with emphysema. He discusses the procedure, patient outcomes, and which patients should be considered for BLVR.  

--

Associate Professor of Medicine, Henry Ford Hospital, Wayne State University; Program Director, Interventional Pulmonology Fellowship, Henry Ford Health System, Detroit, MI

Javier Diaz-Mendoza, MD, FCCP, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Ion Intuitive Serve(d) as a speaker or a member of a speakers bureau for: Association of Interventional Pulmonology Program Directors

Patients with chronic obstructive pulmonary disease (COPD) typically have emphysema, which involves destruction of alveoli and reduction of elasticity leading to airflow obstruction, air trapping, and hyperinflation. Over time, these changes cause low respiratory reserve volume and increased residual volume, which cause dyspnea.  

One of the newest treatment options for patients who have advanced COPD with severe emphysema is a minimally invasive procedure called bronchoscopic lung volume reduction (BLVR). Most recently, the FDA approved the use of endobronchial valves for this procedure, which are implanted in the airways of the lungs to reduce air trapping and hyperinflation. 

In certain patients, BLVR has been shown to improve lung function, facilitate easier breathing, enhance exercise tolerance, and lead to better quality of life. 

In this ReCAP, Dr. Javier Diaz-Mendoza, program director of the Interventional Pulmonology Fellowship at Henry Ford Health System in Detroit, discusses the benefits of BLVR in patients who have advanced COPD with emphysema. He discusses the procedure, patient outcomes, and which patients should be considered for BLVR.  

--

Associate Professor of Medicine, Henry Ford Hospital, Wayne State University; Program Director, Interventional Pulmonology Fellowship, Henry Ford Health System, Detroit, MI

Javier Diaz-Mendoza, MD, FCCP, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Ion Intuitive Serve(d) as a speaker or a member of a speakers bureau for: Association of Interventional Pulmonology Program Directors

Zelnorm (tegaserod), an oral short-term treatment of irritable bowel syndrome and constipation (IBS-C), is being removed from the U.S. market effective June 30, according to the manufacturer, Alfasigma.

The Italian pharmaceutical company said the drug is being removed for business purposes, not because of any concern involving its safety or efficacy, nor has it been recalled.

The drug has been through a teeter totter of regulations since its inception.

When it was first introduced in 2002, Zelnorm was a first-of-its-kind drug and was intended to treat all women with IBS-C in the short term. But it was removed from the market 5 years later following concerns about cardiovascular side effects. Clinical data showed an increased incidence of stroke and angina in women taking Zelnorm.

Despite these concerns, the U.S. Food and Drug Administration voted to reintroduce the drug into the market in 2019, but only for women without a history of heart health problems.

Though Alfasigma will stop making the drug, a company news release said current users can continue use for a while.

“Patients will continue to have access to Zelnorm (tegaserod) for as long as the existing supply of product remains in the trade channel,” Alfasigma said in a news release about the drug removal. The company urged its customers to discuss alternative IBS medications with their doctor.

Zelnorm is a serotonin agonist, meaning it binds to receptors and stops the release of serotonin into the system. These sorts of drugs can decrease the pain associated with IBS and help increase gut motility in order to pass stool. Other drugs besides Zelnorm that use this mechanism include alosetron and cilansetron.

A version of this article first appeared on Medscape.com.

Zelnorm (tegaserod), an oral short-term treatment of irritable bowel syndrome and constipation (IBS-C), is being removed from the U.S. market effective June 30, according to the manufacturer, Alfasigma.

The Italian pharmaceutical company said the drug is being removed for business purposes, not because of any concern involving its safety or efficacy, nor has it been recalled.

The drug has been through a teeter totter of regulations since its inception.

When it was first introduced in 2002, Zelnorm was a first-of-its-kind drug and was intended to treat all women with IBS-C in the short term. But it was removed from the market 5 years later following concerns about cardiovascular side effects. Clinical data showed an increased incidence of stroke and angina in women taking Zelnorm.

Despite these concerns, the U.S. Food and Drug Administration voted to reintroduce the drug into the market in 2019, but only for women without a history of heart health problems.

Though Alfasigma will stop making the drug, a company news release said current users can continue use for a while.

“Patients will continue to have access to Zelnorm (tegaserod) for as long as the existing supply of product remains in the trade channel,” Alfasigma said in a news release about the drug removal. The company urged its customers to discuss alternative IBS medications with their doctor.

Zelnorm is a serotonin agonist, meaning it binds to receptors and stops the release of serotonin into the system. These sorts of drugs can decrease the pain associated with IBS and help increase gut motility in order to pass stool. Other drugs besides Zelnorm that use this mechanism include alosetron and cilansetron.

A version of this article first appeared on Medscape.com.

Zelnorm (tegaserod), an oral short-term treatment of irritable bowel syndrome and constipation (IBS-C), is being removed from the U.S. market effective June 30, according to the manufacturer, Alfasigma.

The Italian pharmaceutical company said the drug is being removed for business purposes, not because of any concern involving its safety or efficacy, nor has it been recalled.

The drug has been through a teeter totter of regulations since its inception.

When it was first introduced in 2002, Zelnorm was a first-of-its-kind drug and was intended to treat all women with IBS-C in the short term. But it was removed from the market 5 years later following concerns about cardiovascular side effects. Clinical data showed an increased incidence of stroke and angina in women taking Zelnorm.

Despite these concerns, the U.S. Food and Drug Administration voted to reintroduce the drug into the market in 2019, but only for women without a history of heart health problems.

Though Alfasigma will stop making the drug, a company news release said current users can continue use for a while.

“Patients will continue to have access to Zelnorm (tegaserod) for as long as the existing supply of product remains in the trade channel,” Alfasigma said in a news release about the drug removal. The company urged its customers to discuss alternative IBS medications with their doctor.

Zelnorm is a serotonin agonist, meaning it binds to receptors and stops the release of serotonin into the system. These sorts of drugs can decrease the pain associated with IBS and help increase gut motility in order to pass stool. Other drugs besides Zelnorm that use this mechanism include alosetron and cilansetron.

A version of this article first appeared on Medscape.com.